Hippocampal GABAergic Inhibitory Interneurons
Open accessAbstract
In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population; however, their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and circuit function. Here we provide an overview of the current state of the field of interneuron research, focusing largely on the hippocampus. We discuss recent advances related to the various cell types, including their development and maturation, expression of subtype-specific voltage- and ligand-gated channels, and their roles in network oscillations. We also discuss recent technological advances and approaches that have permitted high-resolution, subtype-specific examination of their roles in numerous neural circuit disorders and the emerging therapeutic strategies to ameliorate such pathophysiological conditions. The ultimate goal of this review is not only to provide a touchstone for the current state of the field, but to help pave the way for future research by highlighting where gaps in our knowledge exist and how a complete appreciation of their roles will aid in future therapeutic strategies.
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Written from a shortened version of the paper’s full text (it is longer than we read).
TL;DR
This review synthesizes current knowledge on hippocampal GABAergic inhibitory interneurons, covering their anatomical and physiological diversity, developmental origins, synaptic properties, circuit roles, and links to disease. It emphasizes that although interneurons are only ~10–15% of hippocampal neurons, their subtype-specific organization allows them to regulate virtually all aspects of cellular and circuit function.
Key findings
- Hippocampal GABAergic interneurons account for ~10–15% of the total neuronal population; in a 30-day-old Wistar rat, CA1 is estimated to contain ~350,000 neurons, including ~38,500 inhibitory interneurons.
- Major CA1 interneuron subtypes have distinct estimated abundances: PVBCs ~14% (~5,530 cells), CCKBCs ~9% (~3,600), Ivy cells ~23% (8,800), NGFCs ~9% (~3,600), BiCs ~6% (~2,200), O-LM cells ~4.5% (~1,650), AACs ~4% (~1,500), and interneuron-selective interneurons ~20%.
- Developmental origins are subtype-linked: MGE produces ~60% of neocortical and hippocampal interneurons, CGE ~30%, and POA ~10%; some hippocampal SST-expressing and NGFC populations show dual MGE/CGE origins.
- Interneuron subtypes differ in intrinsic physiology and release properties: PV-containing cells are fast-spiking with brief action potentials (~0.5 ms) and can fire >100 Hz, whereas CCK-containing cells show asynchronous release and NGFCs mediate volume transmission with slow GABAergic inhibition.
Methods
- Design: narrative review and synthesis of the hippocampal inhibitory interneuron literature, not a primary experimental study.
- Data/sample: primarily rodent (mouse and rat) hippocampal CA1, with comparisons to CA3, dentate gyrus, neocortex, and mention of human/primate findings; quantitative estimates are drawn from cited studies such as Bezaire and Soltesz and Tricoire et al.
- Main analysis: organizes findings by anatomy, development, intrinsic physiology, glutamate/GABA receptors, synaptic plasticity, endocannabinoids, and circuit function, using cited datasets, tables, and figures rather than new data collection.
Limitations
- The authors state that it is impossible to discuss every aspect of the field fully and that only a small number of cell types have been systematically explored in depth, leaving many interneurons incompletely studied.
- The review notes that comparing physiological parameters across studies is difficult because slice preparation, intracellular solutions, recording quality, and access resistance can alter resting potential and channel properties.
- As a review, it presents no new primary data; conclusions depend on cited literature, and much of the synthesis is based on rodent CA1, which may not fully generalize to other regions or species.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Premisecitation§ Abstract
In the hippocampus, GABAergic local circuit inhibitory interneurons represent only ~10-15% of the total neuronal population.
“In the hippocampus GABAergic local circuit inhibitory interneurons represent only ~10–15% of the total neuronal population”
- Also stated in: § I. INTRODUCTION · plain
“In hippocampus, GABAergic local circuit inhibitory interneurons account for ~10–15% of the total neuronal cell population.”
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- Also stated in: § I. INTRODUCTION · plain
- Premisecitation§ II. ANATOMY
Parvalbumin (PV) is generally considered a core molecular marker for mature AACs, with immunolabeling detectable throughout their somatodendritic and axonal compartments.
“Generally, the calcium binding protein parvalbumin (PV) is considered a core molecular marker for mature AACs with immunolabeling detectable throughout their somatodendritic and axonal compartments (FIGURE 2A) (74, 352, 563, 1036, 1041).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ II. ANATOMY
Throughout hippocampus and neocortex, selective innervation of axon initial segments by AACs provides control over principal cell spike generation.
“Thus, throughout hippocampus and neocortex, selective innervation of axon initial segments by AACs provides exquisite control over principal cell spike generation.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ II. ANATOMY
AACs account for ~5% of MGE-derived hippocampal interneurons.
“AACs account for ~5% of MGE-derived hippocampal interneurons since AACs represent 15% of all PV interneurons (102, 1137).”
Quote in the paperNot a substantial claim0 of 2 sources checked- The authors state this as an assumption: MGE-derived interneurons account for ~60% of all CA1 interneurons, with relative contributions of 35/25/40% from PV, somatostatin, and neurogliaform/Ivy interneuron cohorts, respectively.
- Interpretationcitation§ II. ANATOMY
Anatomical specialization among cortical interneuron subtypes allows for a division of labor that affords inhibitory networks spatiotemporal control over principal cell activity, rather than providing generalized inhibition.
“Indeed, it is now recognized that anatomical specialization among cortical interneuron subtypes allows for a division of labor that affords inhibitory networks exquisite spatiotemporal control over principal cell activity, rather than providing generalized inhibition (586, 1036).”
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- Premisecitation§ II. ANATOMY
AAC axons densely arborize throughout stratum pyramidale and superficial stratum oriens with terminals exclusively targeting the axon initial segments of up to 1,200 pyramidal cells.
“The axon originates from the soma or a primary dendrite and densely arborizes throughout s.p. and superficial s.o. with terminals exclusively targeting the axon initial segments of up to 1,200 pyramidal cells (FIGURE 2A) (135, 676, 1037).”
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In contrast to other basket cells (all PVBCs and CA1-3 CCKBCs), dentate CCKBC terminals preferentially innervate proximal dendrites with minimal contacts onto postsynaptic target somas.
“In contrast to other basket cells (all PVBCs and CA1–3 CCKBCs), dentate CCKBC terminals preferentially innervate proximal dendrites with minimal contacts onto postsynaptic target somas.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
The defining anatomical feature of CCKBCs is preferential perisomatic axonal targeting within stratum pyramidale to surround the soma and proximal dendrites of pyramidal cells.
“Like PVBCs, the defining anatomical feature of CCKBCs is preferential perisomatic axonal targeting within s.p. to surround the soma and proximal dendrites of pyramidal cells (FIGURE 2E) (224, 352, 584, 1036, 1172).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ C. Bistratified Cells
CCKBCs account for 20% of CGE-derived interneurons.
“CCKBCs account for 20% of CGE-derived interneurons as CCKBC comprise 65% of all CCK+ interneurons (102, 203, 1138).”
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- The authors state this as an assumption: CGE-derived interneurons account for ~40% of all CA1 interneurons, with relative contributions of 30/30/25/10% from CCK+ interneurons, interneuron selective interneurons, neurogliaform interneurons, SST+ interneurons, respectively, and a remaining 5% of unidentified interneurons.
- Premisecitation§ C. Bistratified Cells
All hippocampal and cortical CCKBCs have origin in the caudal ganglionic eminence (CGE).
“All hippocampal and cortical CCKBCs have origin in the caudal ganglionic eminence (CGE) (203, 651, 805, 1138, 1204).”
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The defining molecular characteristic of CCKBCs is the expression of the octapeptide form of the CCK neuropeptide (CCK-8) throughout the somatodendritic and axonal compartments of CCKBCs.
“As the name implies, the defining molecular characteristic of CCKBCs is the expression of the octapeptide form of the CCK neuropeptide (CCK-8) throughout the somatodendritic and axonal compartments of CCKBCs (352, 355, 467, 843).”
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CCK expression can be detected in a variety of dendrite targeting inhibitory interneurons that largely parse on the basis of axon termination zones across distinct pyramidal cell dendritic compartments.
“In addition to CCKBCs, CCK expression can also be detected in a variety of dendrite targeting inhibitory interneurons that largely parse on the basis of axon termination zones across distinct pyramidal cell dendritic compartments (102, 581, 1036).”
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Like CCKBCs, dendrite targeting CCK interneuron subtypes typically express CB1Rs.
“Like CCKBCs, dendrite targeting CCK interneuron subtypes typically express CB1Rs (FIGURE 3B) (108, 289, 584, 594, 665, 1194).”
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The axonal projections of SCAs co-align with glutamatergic inputs from CA3, ramifying dominantly within s.r. and to a lesser extent in s.o. to primarily target the oblique and basal dendrites of pyramidal cells.
“The axonal projections of Schaffer collateral-associated cells (SCAs) co-align with glutamatergic inputs from CA3, ramifying dominantly within s.r. and to a lesser extent in s.o. to primarily target the oblique and basal dendrites of pyramidal cells (FIGURE 3B).”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
PPAs also extend axon collaterals across the hippocampal fissure to target the dendrites of granule cells further aligning their output with excitatory entorhinal input to the hippocampus.
“However, PPAs also extend axon collaterals across the hippocampal fissure to target the dendrites of granule cells further aligning their output with excitatory entorhinal input to the hippocampus (452, 584, 1172).”
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CCK-expressing dendrite targeting interneurons together comprise between 3 and 5% (~1,500 cells) of CA1 interneurons (~0.4% of all CA1 neurons).
“CCK-expressing dendrite targeting interneurons together comprise between 3 and 5% (~1,500 cells) of CA1 interneurons (~0.4% of all CA1 neurons), largely reside in s.r., with some tendency to concentrate at the s.r./s.l.m. border.”
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The axons of PPAs concentrate within s.l.m. overlapping with excitatory inputs from the entorhinal cortex and nucleus reuniens targeting the distal apical tufts of CA1 pyramidal cells.
“The axons of perforant path-associated cells (PPAs) concentrate within s.l.m. overlapping with excitatory inputs from the entorhinal cortex and nucleus reuniens targeting the distal apical tufts of CA1 pyramidal cells (584, 1172).”
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Combinatorial genetic approaches do not allow for selective targeting of CCKBCs, as a number of CCK-expressing dendrite-innervating interneurons will also be targeted.
“However, as exciting as these refinements are, they do not allow for selective targeting of CCKBCs as a number of CCK-expressing dendrite-innervating interneurons will also be targeted using these combinatorial genetic approaches (see below).”
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A minority (~8%) of CCK-expressing dendrite targeting cell terminals innervate other interneurons.
“All CCK-expressing dendrite targeting cells dominantly target principal cell postsynaptic targets with ~6 synapses per connection; however, a minority of terminals (~8%) innervate other interneurons (102, 224, 584, 1172).”
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In both neocortex and hippocampus, all CCK-expressing interneurons have so far been found to arise from the CGE (10% of CGE-derived interneurons based on assumptions outlined above).
“However, in both neocortex and hippocampus, all CCK-expressing interneurons have so far been found to arise from the CGE (10% of CGE-derived interneurons based on assumptions outlined above) (102, 203, 651, 1138).”
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HIPPs are optimally positioned to participate in a feedback inhibitory loop gating excitatory drive from extrahippocampal projections to the distal dendrites of their principal cell targets.
“As in CA1, HIPPs are optimally positioned to participate in a feedback inhibitory loop gating excitatory drive from extrahippocampal projections to the distal dendrites of their principal cell targets.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
The dentate gyrus O-LM equivalent is the hilar perforant path associated cell (HIPP).
“The dentate gyrus O-LM equivalent is the hilar perforant path associated cell (HIPP) (352, 461, 499, 980, 1013).”
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A minority of O-LM terminals (~10%) innervate other interneurons in s.o., at the s.r/s.l.m border, and within s.l.m.
“A minority of O-LM terminals (~10%) innervate other interneurons in s.o., at the s.r/s.l.m border, and within s.l.m. (102, 299, 559, 592).”
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O-LMs are named for their striking anatomy with soma and dendrites restricted to s.o. and the alveus while the axon ascends with minimal branching through s.p. and s.r. to densely collateralize within s.l.m.
“O-LMs are named for their striking anatomy with soma and dendrites restricted to s.o. and the alveus while the axon ascends with minimal branching through s.p. and s.r. to densely collateralize within s.l.m. (FIGURE 3C) (352, 719, 721, 768, 1014).”
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The defining molecular characteristic of mature O-LM, HIPP, and Martinotti cells is the expression of SST.
“The defining molecular characteristic of mature O-LM, HIPP, and Martinotti cells is the expression of SST (FIGURE 3C) (352, 571, 581, 716, 721, 862, 980, 1134, 1154).”
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- Premisecitation§ C. Bistratified Cells
O-LM axon sprouting into the dentate gyrus has been reported in an animal model of epilepsy.
“In contrast to CCK-expressing PPA cells (see above) and the recently described CA1 SOM-containing back projection neuron (562), the axon of O-LM cells does not cross the hippocampal fissure to invade the dentate gyrus in the healthy brain; however, O-LM axon sprouting into the dentate gyrus has been reported in an animal model of epilepsy (894).”
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- Premisecitation§ C. Bistratified Cells
The axon of O-LM cells does not cross the hippocampal fissure to invade the dentate gyrus in the healthy brain.
“In contrast to CCK-expressing PPA cells (see above) and the recently described CA1 SOM-containing back projection neuron (562), the axon of O-LM cells does not cross the hippocampal fissure to invade the dentate gyrus in the healthy brain; however, O-LM axon sprouting into the dentate gyrus has been reported in an animal model of epilepsy (894).”
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- Premisecitation§ C. Bistratified Cells
O-LMs are estimated to comprise ~4.5% (~1650 cells) of hippocampal CA1 interneurons (0.5% of all CA1 neurons).
“Oriens lacunosum-moleculare interneurons (O-LMs) are estimated to comprise ~4.5% (~1650 cells) of hippocampal CA1 interneurons (0.5% of all CA1 neurons) (102).”
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- Premisecitation§ C. Bistratified Cells
The neocortical homolog of the O-LM cell is the Martinotti cell typically encountered in layers 2/3 and 5/6 with ascending axon forming a plexus in layer 1 targeting the distal dendritic tufts of pyramidal cells.
“The neocortical homolog of the O-LM cell is the Martinotti cell typically encountered in layers 2/3 and 5/6 with ascending axon forming a plexus in layer 1 targeting the distal dendritic tufts of pyramidal cells (569, 571, 1134, 1154, 1192).”
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This anatomical arrangement optimally positions O-LMs to function in a prototypical feedback inhibitory circuit.
“This anatomical arrangement optimally positions O-LMs to function in a prototypical feedback inhibitory circuit.”
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Further divergence in O-LM and Martinotti cell molecular profiles is evidenced by the frequent coexpression of CR with SST in Martinotti cells, a molecular signature that is absent from the hippocampus.
“Further divergence in O-LM and Martinotti cell molecular profiles is evidenced by the frequent coexpression of CR with SST in Martinotti cells, a molecular signature that is absent from the hippocampus (203, 339, 1042, 1238).”
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SST-expressing interneurons can be genetically accessed in developing and mature brains using SST-Cre driver lines.
“In general, SST-expressing interneurons can be genetically accessed in developing and mature brains using SST-Cre driver lines (702, 1096).”
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Somatodendritic labeling for Elfn1 is suggested to be specific for O-LMs.
“Similarly, somatodendritic labeling for the extracellular leucine-rich repeat fibronectin containing 1 protein (Elfn1) is suggested to be specific for O-LMs (561, 1073).”
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Several primary dendrites extend from the soma then branch extensively in a stellate fashion yielding a compact somatodendritic profile reminiscent of glial cells that is typically fully contained within the NGFC's local axon cloud.
“Several primary dendrites extend from the soma then branch extensively in a stellate fashion yielding a compact somatodendritic profile reminiscent of glial cells that is typically fully contained within the NGFC’s local axon cloud (FIGURE 3D; Refs. 299, 367, 550, 578, 606, 926, 1137, 1172, 1280).”
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- Premisecitation§ C. Bistratified Cells
NGFCs are estimated to make up just over 9% (~3,600 cells) of the entire CA1 hippocampal interneuron population (1% of all CA1 neurons).
“Neurogliaform cells (NGFCs) are estimated to make up just over 9% (~3,600 cells) of the entire CA1 hippocampal interneuron population (1% of all CA1 neurons) (102).”
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- Premisecitation§ C. Bistratified Cells
In CA1, the small spherical somas (~15 μm in diameter) of NGFCs are typically found in s.l.m. with a minority of cells residing at the s.l.m./s.r. border and superficial s.r.
“In CA1, the small spherical somas (~15 µm in diameter) of NGFCs are typically found in s.l.m. with a minority of cells residing at the s.l.m./s.r. border and superficial s.r. (46, 165, 870).”
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In the hippocampus, a conspicuously high level of mGluR1α immunoreactivity along their horizontal dendrites further helps to molecularly identify O-LM cells.
“In the hippocampus, a conspicuously high level of metabotropic glutamate receptor 1α (mGluR1α) immunoreactivity along their horizontal dendrites further helps to molecularly identify O-LM cells (75, 324, 581, 582, 1142).”
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Off-target recombination in non-SST-expressing interneurons and even in pyramidal cells has been reported using SST-Cre lines.
“Moreover, off-target recombination in non-SST-expressing interneurons and even in pyramidal cells has been reported using SST-Cre lines (501, 787).”
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Given the diversity in SST-expressing interneurons throughout the neocortex and hippocampus, these lines cannot be used for selective targeting of O-LM, HIPP, and Martinotti cells.
“However, given the diversity in SST-expressing interneurons throughout the neocortex and hippocampus, these lines cannot be used for selective targeting of O-LM, HIPP, and Martinotti cells (102, 535, 536, 716, 862, 1154).”
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These features combined with the dense local ramification of NGFC axons are considered to underlie the ability of NGFCs to mediate volume transmission leading to slow dual component (GABAAR- and GABABR-mediated) inhibition at virtually any postsynaptic element within their dense axonal plexus.
“These features combined with the dense local ramification of NGFC axons are considered to underlie the ability of NGFCs to mediate volume transmission leading to slow dual component (GABAAR- and GABABR-mediated) inhibition at virtually any postsynaptic element within their dense axonal plexus (550, 926, 927, 1074, 1086).”
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Neocortical NGFCs have singular origins within the CGE.
“In contrast, neocortical NGFCs have singular origins within the CGE (651, 796, 1179).”
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Molecular markers associated with NGFCs include NPY, reelin, neuronal nitric oxide synthase (nNOS), α-actinin 2, and COUP transcription factor 2 (COUPTF2).
“Molecular markers associated with NGFCs include NPY, reelin, neuronal nitric oxide synthase (nNOS), α-actinin 2, and COUP transcription factor 2 (COUPTF2) (48, 367, 549, 796, 858, 926, 1137).”
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Molecular identification of NGFCs is complicated by considerable heterogeneity such that no one marker or combination of markers uniquely or comprehensively reveals the entire NGFC cohort.
“However, molecular identification of NGFCs is complicated by considerable heterogeneity such that no one marker or combination of markers uniquely or comprehensively reveals the entire NGFC cohort.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ C. Bistratified Cells
The strong affiliation of most CA1 NGFC input and output elements with s.l.m. optimally positions them to primarily serve a feedforward inhibitory role in gating excitatory input from the entorhinal cortex and nucleus reuniens.
“The strong affiliation of most CA1 NGFC input and output elements with s.l.m. optimally positions them to primarily serve a feedforward inhibitory role in gating excitatory input from the entorhinal cortex and nucleus reuniens.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
Some NGFCs near the s.r./s.l.m border appear to demonstrate stronger affiliation with the Schaffer collateral pathway.
“Moreover, some NGFCs near the s.r./s.l.m border appear to demonstrate stronger affiliation with the Schaffer collateral pathway (606, 1138, 1172).”
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Even at synaptic junctions with identifiable postsynaptic elements (typically principal cell spines, spine necks, or dendritic shafts), NGFC inputs exhibit a strikingly wide synaptic cleft.
“Even at synaptic junctions with identifiable postsynaptic elements (typically principal cell spines, spine necks, or dendritic shafts), NGFC inputs exhibit a strikingly wide synaptic cleft (858).”
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- Premisecitation§ C. Bistratified Cells
An unusual anatomical feature of NGFCs is their remarkably high density of small area en passant boutons that in many cases (50-75% of terminals) do not have clear postsynaptic targets.
“An unusual anatomical feature of NGFCs is their remarkably high density of small area en passant boutons that in many cases (50–75% of terminals) do not have clear postsynaptic targets (102, 858, 1172).”
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Despite occupying a relatively small tissue volume, the total axon length of an individual NGFC is estimated to be greater than three times that of a typical PVBC.
“Indeed, despite occupying a relatively small tissue volume, the total axon length of an individual NGFC is estimated to be greater than three times that of a typical PVBC (102, 870).”
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In CA1 hippocampus differential expression of nNOS by NGFCs correlates to distinct embryonic origins.
“In CA1 hippocampus differential expression of nNOS by NGFCs correlates to distinct embryonic origins.”
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VIP and CR coexpressing type 3 ISIs (ISI-3s) have fusiform cell bodies typically residing in s.p. and deep s.r.
“VIP and CR coexpressing type 3 ISIs (ISI-3s) have fusiform cell bodies typically residing in s.p. and deep s.r. (5, 6, 185, 439, 1145).”
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In contrast to pyramidal cell targeting interneurons, terminal distribution along ISI-1 axons (and all ISIs) is highly uneven with large lengths of axon exhibiting few boutons interspersed with sections of high bouton density upon encountering appropriate GABAergic postsynaptic elements.
“In contrast to pyramidal cell targeting interneurons, terminal distribution along ISI-1 axons (and all ISIs) is highly uneven with large lengths of axon exhibiting few boutons interspersed with sections of high bouton density upon encountering appropriate GABAergic postsynaptic elements.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
Initial anatomical studies revealed that the major postsynaptic targets of ISI-3s are the horizontal running dendrites of SST- and mGluR1α-expressing O-LMs with which individual ISI-3s form multiple synaptic contacts.
“Indeed, initial anatomical studies revealed that the major postsynaptic targets of ISI-3s are the horizontal running dendrites of SST- and mGluR1α-expressing O-LMs with which individual ISI-3s form multiple synaptic contacts.”
Quote in the paperSubstantial claim - Premisenone given§ C. Bistratified Cells
Anatomical observations indicate that ISI-1s essentially avoid PV expressing interneurons and pyramidal cells.
“In contrast, anatomical observations indicate that ISI-1s essentially avoid PV expressing interneurons and pyramidal cells.”
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The majority of these cells have a characteristic smooth or sparsely spiny dendritic tree comprised of a tuft restricted to s.l.m. positioning them for recruitment primarily by entorhinal and reuniens input.
“The majority of these cells have a characteristic smooth or sparsely spiny dendritic tree comprised of a tuft restricted to s.l.m. positioning them for recruitment primarily by entorhinal and reuniens input.”
Quote in the paperNot a substantial claim - Premiseown data§ C. Bistratified Cells
In contrast to the other ISIs, the main axon primarily descends to s.o. where it emits several long horizontal collaterals producing a dense plexus within deep s.o. and the alveus co-aligning with the horizontal dendrites of oriens residing interneurons.
“In contrast to the other ISIs, the main axon primarily descends to s.o. where it emits several long horizontal collaterals producing a dense plexus within deep s.o. and the alveus co-aligning with the horizontal dendrites of oriens residing interneurons (FIGURE 3F).”
Quote in the paperSubstantial claim - Premisecitation§ C. Bistratified Cells
A subset of IvCs located in superficial s.r. has been found to extend significant dendritic and axonal process into s.l.m. blurring the lines between the input and output domains of IvCs and NGFCs.
“However, a subset of IvCs located in superficial s.r. has been found to extend significant dendritic and axonal process into s.l.m. blurring the lines between the input and output domains of IvCs and NGFCs (1032).”
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- Premisenone given§ C. Bistratified Cells
Upon encountering these cells, individual axons frequently form multiple contacts in a climbing fiber-like manner along their dendrites or soma.
“Upon encountering these cells, individual axons frequently form multiple contacts in a climbing fiber-like manner along their dendrites or soma.”
Quote in the paperNot a substantial claim - Premisenone given§ C. Bistratified Cells
While each of the interneuron subtypes described thus far exhibits some degree of connectivity among themselves and other interneurons, these homotypic and heterotypic interneuron-interneuron connections represent a minority of their outputs (~5-15%) compared with their innervation of pyramidal cells.
“While each of the interneuron subtypes described thus far exhibits some degree of connectivity among themselves and other interneurons, these homotypic and heterotypic interneuron-interneuron connections represent a minority of their outputs (~5–15%) compared with their innervation of pyramidal cells.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ C. Bistratified Cells
Thus recruitment of ISI-3s is expected to primarily disinhibit O-LM-mediated feedback inhibition of the most distal apical dendritic elements of CA1 pyramidal cells in the termination zone of entorhinal and reuniens afferent input.
“Thus recruitment of ISI-3s is expected to primarily disinhibit O-LM-mediated feedback inhibition of the most distal apical dendritic elements of CA1 pyramidal cells in the termination zone of entorhinal and reuniens afferent input.”
Quote in the paperSubstantial claim - Interpretationreasoning§ C. Bistratified Cells
Like ISI-3s, such dentate ISIs appear specialized to disinhibit the distal dendrites of local principal cells, the granule cells, in the termination zone of perforant path inputs from the entorhinal cortex.
“Thus, like ISI-3s, such dentate ISIs appear specialized to disinhibit the distal dendrites of local principal cells, the granule cells, in the termination zone of perforant path inputs from the entorhinal cortex.”
Quote in the paperNot a substantial claim - Premisenone given§ C. Bistratified Cells
ISI-3 dendritic trees are typically bipolar spanning all strata with a prominent tuft of several horizontally running branches in s.l.m.
“ISI-3 dendritic trees are typically bipolar spanning all strata with a prominent tuft of several horizontally running branches in s.l.m.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
In the dentate gyrus, VIP and CR coexpressing interneurons homologous to ISI-3s are the most frequently encountered ISIs.
“In the dentate gyrus, VIP and CR coexpressing interneurons homologous to ISI-3s are the most frequently encountered ISIs (352, 449).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ C. Bistratified Cells
Thus recruitment of ISI-1s by Schaffer collateral, entorhinal, reuniens, or CA1 pyramid collateral input is expected to preferentially disinhibit the apical dendrites of CA1 pyramidal cells within the termination zone of CA3 Schaffer collateral input.
“Thus recruitment of ISI-1s by Schaffer collateral, entorhinal, reuniens, or CA1 pyramid collateral input is expected to preferentially disinhibit the apical dendrites of CA1 pyramidal cells within the termination zone of CA3 Schaffer collateral input.”
Quote in the paperSubstantial claim - Premisecitation§ C. Bistratified Cells
A distinct family of interneurons selectively or preferentially innervates other interneurons providing a cellular substrate specialized for network disinhibition.
“In contrast, a distinct family of interneurons selectively or preferentially innervates other interneurons providing a cellular substrate specialized for network disinhibition.”
Quote in the paperSubstantial claim - Premisecitation§ C. Bistratified Cells
More recently, a number of functional studies in both hippocampus and neocortex have taken advantage of transgenic animals and modern circuit mapping tools to functionally confirm that subsets of CR- and VIP-expressing interneurons do indeed mediate circuit disinhibition by selectively targeting other interneurons over pyramidal cells.
“More recently, a number of functional studies in both hippocampus and neocortex have taken advantage of transgenic animals and modern circuit mapping tools to functionally confirm that subsets of CR- and VIP-expressing interneurons do indeed mediate circuit disinhibition by selectively targeting other interneurons over pyramidal cells (185, 363, 652, 906, 908, 1145, 1270).”
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- cites [363] source
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- cites [652] source
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- cites [906] source
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- cites [908] source
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- cites [1145] source
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- cites [1270] source
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- Premisereasoning§ C. Bistratified Cells
The output of ISI-2s further resembles that of ISI-1s in essentially avoiding PV-expressing interneurons and pyramidal cells as postsynaptic partners.
“The output of ISI-2s further resembles that of ISI-1s in essentially avoiding PV-expressing interneurons and pyramidal cells as postsynaptic partners.”
Quote in the paperSubstantial claim - Premisecitation§ C. Bistratified Cells
A unique feature of ISI-1s is the regular occurrence of long dendrodendritic junctions in which two to seven dendrites from separate ISI-1s are intermingled for more than 100 μm frequently with varicose axons of additional ISI-1s.
“A unique feature of ISI-1s is the regular occurrence of long dendrodendritic junctions in which two to seven dendrites from separate ISI-1s are intermingled for more than 100 µm frequently with varicose axons of additional ISI-1s (439).”
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- Premisenone given§ C. Bistratified Cells
The axons of ISI-1s ramify within s.r., s.p., and sparsely within s.o. seeking out somatodendritic compartments of interneuron targets.
“The axons of ISI-1s ramify within s.r., s.p., and sparsely within s.o. seeking out somatodendritic compartments of interneuron targets.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
Type 1 ISIs (ISI-1s) are CR-expressing multipolar cells with somas found throughout s.r, s.p., and s.o.
“Type 1 ISIs (ISI-1s) are CR-expressing multipolar cells with somas found throughout s.r, s.p., and s.o. (439, 1145).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given§ C. Bistratified Cells
A subpopulation of ISI-2s exhibit bipolar radially oriented dendrites spanning all strata, suggesting overlap in function with ISI-1s.
“However, a subpopulation of ISI-2s exhibit bipolar radially oriented dendrites spanning all strata, suggesting overlap in function with ISI-1s.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
There are clear correlations between birthdate and ultimate interneuron subtype identity.
“Thus there are clear correlations between birthdate and ultimate interneuron subtype identity.”
Quote in the paperNot a substantial claim - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Both SST- and PV-expressing interneurons are produced in varying proportions during the dominant period of MGE neurogenesis between E9.5 and E15.5.
“both SST- and PV-expressing interneurons are produced in varying proportions during the dominant period of MGE neurogenesis between E9.5 and E15.5”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
In the hippocampus, SST and PV interneurons both exhibit peaks in their genesis around E11.5.
“In the hippocampus SST and PV interneurons both exhibit peaks in their genesis around E11.5”
Quote in the paperNot a substantial claim - Interpretationcitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Temporal dynamics only partially predict ultimate interneuron identity.
“temporal dynamics only partially predict ultimate interneuron identity”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
E16.5 Nkx2.1-expressing donor cells transplanted into the somatosensory cortex of P3 hosts reliably differentiated into AACs.
“when E16.5 Nkx2.1 expressing donor cells were transplanted into the somatosensory cortex of P3 hosts, they reliably differentiated into AACs”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
SST hub cells are generated from Nkx2.1 progenitors at E9.5, before the MGE is morphologically distinguishable.
“SST hub cells are generated from Nkx2.1 progenitors at the earliest time points of interneuron production (E9.5) before the MGE is even morphologically distinguishable”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
The mode of progenitor mitosis critically influences MGE-derived interneuron fate determination.
“the mode of progenitor mitosis critically influences MGE-derived interneuron fate determination”
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- Premisenone given§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Neocortical PV-expressing interneuron production peaks around E13.5.
“while neocortical PV expressing interneuron production peaks around E13.5”
Quote in the paperNot a substantial claim - Interpretationcitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Late MGE progenitors are fate committed to generating AACs by an intrinsic genetic program late in embryogenesis.
“implying that late MGE progenitors are fate committed to generating AACs by an intrinsic genetic program late in embryogenesis”
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- Interpretationreasoning§ C. Bistratified Cells
In both regions the inclusion of VIP-expressing CCKBCs when using VIP-Cre driver mice is a potential confound to data interpretation at circuit and whole animal level investigations.
“In both regions the inclusion of VIP-expressing CCKBCs when using VIP-Cre driver mice is a potential confound to data interpretation at circuit and whole animal level investigations.”
Quote in the paperNot a substantial claim - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Temporal dynamics significantly impact mature interneuron fate.
“Complementing the spatial control of interneuron specification within the GEs is a temporal dynamic that has significant impact on mature interneuron fate”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
The remarkable diversity of cortical interneurons directly relates to their spatiotemporal origins from discrete progenitor pools within the developing embryonic telencephalon.
“The remarkable diversity of cortical interneurons directly relates to their spatiotemporal origins from discrete progenitor pools within the developing embryonic telencephalon (71, 227,”
Quote in the paperNot a substantial claim - Premisecitation§ C. Bistratified Cells
Genetic access for manipulation of ISIs is available through use of VIP-Cre and CR-Cre driver lines of mice.
“Genetic access for manipulation of ISIs is available through use of VIP-Cre and CR-Cre driver lines of mice (1096).”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
PV-expressing AAC neurogenesis preferentially occurs beyond E15.5, after the MGE has morphologically flattened into a ventral germinal zone.
“PV-expressing AAC neurogenesis preferentially occurs beyond E15.5 after the MGE has morphologically flattened out into a ventral germinal zone of the lateral ventricle”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisenone given§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
nNOS-expressing IvCs/NGFCs exhibit a later peak in production around E13.5.
“nNOS expressing IvCs/NGFCs exhibit a later peak in production around E13.5”
Quote in the paperNot a substantial claim - Premisenone given§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Within the MGE, SST-expressing interneurons destined for the neocortex exhibit a peak in neurogenesis around E11.5.
“Within the MGE, SST-expressing interneurons destined for the neocortex exhibit a peak in neurogenesis around E11.5”
Quote in the paperNot a substantial claim - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
BP neurogenesis within the SVZ yields primarily PV interneurons.
“BP neurogenesis within the SVZ yields primarily PV interneurons”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Prox1 is differentially required embryonically and postnatally for CGE-derived interneuron migration and differentiation/circuit integration, respectively.
“Loss-of-function studies indicate that Prox1 is differentially required embryonically and postnatally for CGE-derived interneuron migration and differentiation/circuit integration, respectively”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
The CGE produces approximately 30% of neocortical and hippocampal interneurons.
“The CGE produces ~30% of neocortical and hippocampal interneurons”
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- Premisecitation§ C. The Preoptic Area
The POA is estimated to produce approximately 10% of neocortical and hippocampal interneurons.
“The POA is estimated to produce ~10% of neocortical and hippocampal interneurons”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Hippocampal SST interneurons have dual MGE and CGE origins.
“suggesting dual MGE and CGE origins for hippocampal SST interneurons”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
CR-expressing interneuron genesis peaks late at E16.5.
“CR-expressing interneuron genesis peaks late at E16.5”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
In the hippocampus, VIP- and reelin-expressing subsets of CGE-derived interneurons are consistently produced between E12.5 and E16.5.
“in the hippocampus, VIP- and reelin-expressing subsets of CGE derived interneurons are consistently produced between E12.5 and E16.5”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
In contrast to the MGE, the subtypes of neocortical interneurons generated within the CGE do not change significantly over time, with similar proportions of reelin-expressing NGFCs and VIP/CR-expressing ISIs generated across CGE neurogenesis.
“in contrast to the MGE, the subtypes of neocortical interneurons generated within the CGE do not change significantly over time with similar proportions of reelin-expressing NGFCs and VIP/CR-expressing ISIs generated across CGE neurogenesis”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Approximately 40% of hippocampal SST-expressing interneurons are reported in 5-HT3AR-GFP mice.
“~40% of hippocampal SST-expressing interneurons are reported in 5-HT3AR-GFP mice”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [203] source
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Hippocampal NGFCs exhibit dual MGE/CGE origins.
“hippocampal NGFCs exhibit dual MGE/CGE origins”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
O-LM cells significantly contribute to the SST cohorts of both MGE and CGE lineages.
“O-LM cells significantly contribute to the SST cohorts of both lineages”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
CCK-expressing interneurons exhibit an early peak in production around E12.5.
“CCK-expressing interneurons exhibit an early peak in production around E12.5”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
ApP neurogenesis within the MGE VZ is strongly biased to produce SST interneurons.
“ApP neurogenesis within the MGE VZ is strongly biased to produce SST interneurons”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
These 5-HT3AR-GFP-reported hippocampal SST interneurons do not overlap with SST interneurons in the Nkx2.1 lineage.
“these cells do not overlap with SST interneurons in the Nkx2.1 lineage”
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- Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
Transcription factors such as Gsx2, CoupTF1/2, and SP8 are enriched within the CGE and have been implicated in the generation, migration, specification, and maturation of CGE-derived interneurons.
“a number of transcription factors such as Gsx2, CoupTF1/2, and SP8 are enriched within the CGE and have been implicated in the generation, migration, specification, and maturation of CGE-derived interneurons”
Quote in the paperNot a substantial claim0 of 6 sources checked - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
In the neocortex, NGFCs, ISIs, and CCK-expressing interneurons are derived from CGE progenitors.
“In the neocortex NGFCs (reelin-expressing, SST negative), ISIs (VIP- and CR-expressing), and CCK-expressing interneurons (e.g., CCKBCs) are derived from CGE progenitors”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINS
The CGE is a source of cortical interneurons that assume mature fates distinct from MGE-derived interneurons.
“in vitro culture and in vivo transplant studies implicated the CGE as a source of cortical interneurons that assumed mature fates distinct from MGE-derived interneurons”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
Choice of stream is not dependent on lineage, as both MGE- and CGE-derived interneurons can be found in either stream.
“choice of stream is not dependent on lineage, as both MGE- and CGE-derived interneurons can be found in either”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
Cxcl12 acts as an attractant to keep interneurons within the IZ/SVZ and MZ until they reach appropriate maturity to begin radial migration.
“chemokine signaling via Cxcl12, which acts as an attractant to keep interneurons within the IZ/SVZ and MZ until they reach appropriate maturity to begin radial migration”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ C. The Preoptic Area
CGE-derived interneurons express differential combinations of SP8, PROX1, COUPTF1, and COUPTF2 depending on which of the three migratory paths they take.
“CGE-derived interneurons themselves express differential combinations of the transcription factors SP8, PROX1, COUPTF1, and COUPTF2 dependent on which of the three migratory paths they take”
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- Premisecitation§ C. The Preoptic Area
Expression of Nkx2.1 represses transcription of neuropilin-2, a receptor necessary for migrating interneuron repulsion by semaphorin 3F expressed in the striatum.
“Expression of Nkx2.1 represses transcription of neuropilin-2 (842), a receptor necessary for migrating interneuron repulsion by semaphorin 3F expressed in the striatum”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Mature cortical interneurons derived from the POA are highly diverse, consisting of small fractions of PV-, SST-, NPY-, and reelin-expressing interneurons.
“Mature cortical interneurons derived from the POA are highly diverse consisting of small fractions of PV-, SST-, NPY-, and reelin-expressing interneurons”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ C. The Preoptic Area
Interneurons from both GEs converge and disperse via two streams running in parallel, separated by the cortical plate or hippocampal primordium: a deep stream in the IZ/SVZ and a superficial one in the MZ.
“interneurons from both GEs converge and then disperse widely via two streams running in parallel, separated by the cortical plate (CPl) or hippocampal primordium: a deep stream in the intermediate/subventricular zones (IZ/SVZ) and a superficial one in the marginal zone (MZ)”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ C. The Preoptic Area
MGE-derived interneurons can be induced to follow the caudal pathway when forced to overexpress COUPTF2.
“they can be induced to follow the caudal pathway when forced to overexpress COUPTF2, a transcription factor preferentially expressed in the CGE”
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- Premisecitation§ C. The Preoptic Area
GIFM studies using Nkx5.1-Cre mice revealed primarily superficial multipolar mature cortical interneurons expressing NPY and reelin, but not PV, SST, CR, or VIP.
“GIFM studies using Nkx5.1-Cre mice revealed primarily superficial multipolar mature cortical interneurons expressing NPY and reelin, but not other typical interneuron markers such as PV, SST, CR, and VIP”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
MGE-derived interneurons transplanted into the CGE do not join native CGE-derived cells along the caudal pathway, but rather migrate laterally and rostrally.
“MGE-derived interneurons transplanted into the CGE do not join native CGE-derived cells along the caudal pathway, but rather migrate laterally and rostrally”
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- Premisecitation§ C. The Preoptic Area
GIFM studies using Dbx1-Cre mice revealed that the ventral POA region generates minor populations of deep PV- and SST-expressing interneurons.
“GIFM studies using Dbx1-Cre mice revealed that the ventral POA region generates minor populations of deep PV- and SST-expressing interneurons”
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- Premisecitation§ C. The Preoptic Area
Most interneuron precursors emerging from the POA do not rely on downstream activation of Lhx6 to specify PV and SST interneurons.
“most interneuron precursors emerging from the POA do not rely on downstream activation of Lhx6 to specify PV and SST interneurons”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
Two subdomains are found in the POA based on nonoverlapping expression profiles for Dbx1 and Nkx5.1.
“Two subdomains are found in the POA based on nonoverlapping expression profiles for Dbx1 and Nkx5.1”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
Signaling mechanisms involving netrin-1 and GABABRs attract interneurons specifically to the MZ.
“Signaling mechanisms involving netrin-1 and GABABRs attract interneurons specifically to the MZ”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Migrating interneurons initially express low levels of KCC2, which allows GABA to increase motility via depolarization and activation of voltage-gated calcium channels.
“Migrating interneurons initially express low levels of KCC2, which allows GABA to increase motility via depolarization and activation of voltage-gated calcium channels”
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- Premisecitation§ C. The Preoptic Area
In postnatal cortex, Cxcl12 and Cxcr7 expression are maintained preferentially in layer 5.
“In the postnatal cortex, Cxcl12 and Cxcr7 expression are maintained preferentially in layer 5”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Interneurons lacking the reelin receptor Dab1 migrate to the appropriate layer when transplanted into the cortex of wild-type mice.
“interneurons lacking the reelin receptor Dab1 migrate to the appropriate layer when transplanted into the cortex of wild-type mice”
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- Premisecitation§ C. The Preoptic Area
All interneurons, regardless of birthdate or embryonic origin, are initially distributed evenly throughout all layers of cortex and only later migrate to their final laminar position.
“all interneurons, regardless of birthdate or embryonic origin, are initially distributed evenly throughout all layers of cortex and only later migrate to their final laminar position”
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- Premisecitation§ C. The Preoptic Area
Knockout of Cxcl12 results in reduced perisomatic inhibition onto the specific subtype of principal cell in layer 5.
“Knockout of Cxcl12 results in reduced perisomatic inhibition onto this specific subtype of PC in layer 5.”
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- Premisecitation§ C. The Preoptic Area
Embryonic MGE-derived interneurons lacking Cxcr7 transplanted into the cortex at PN1 fail to migrate to layer 5 and instead accumulate in the superficial layers in adult animals.
“when embryonic MGE-derived interneurons lacking Cxcr7 are transplanted into the cortex at PN1, they fail to migrate to layer 5 and instead accumulate in the superficial layers in adult animals”
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- Premisecitation§ C. The Preoptic Area
Choice of layer in both the cortex and hippocampus most strikingly correlates with embryonic origin.
“Choice of layer in both the cortex and hippocampus most strikingly correlates with embryonic origin”
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- Interpretationreasoning§ C. The Preoptic Area
The patterns of radial migration and synaptic connectivity of interneurons strongly depend on their own subtype identity and that of local principal cells.
“Together, these data clearly demonstrate that the patterns of radial migration and synaptic connectivity of interneurons strongly depend on their own subtype identity and that of local PCs.”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
In the cortex of reeler mice, MGE-derived interneurons are inverted similar to principal cells: early-born cells are found ectopically in superficial layers while those born later are found in deep layers.
“In the cortex of reeler mice, MGE-derived interneurons are inverted similar to PCs: early-born cells are found ectopically in superficial layers while those born later are found in the deep layers”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Loss of subcerebral-projecting principal cells correlates with a shift of PV- and SST-expressing interneurons from deep to superficial layers.
“The loss of subcerebral-projecting PCs correlated with a shift of PV- and SST-expressing interneurons from deep to superficial layers”
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- Premisereasoning§ C. The Preoptic Area
This early activity is quickly replaced by synapse-driven network events in which interneurons play a key role via depolarizing actions of GABA on principal cells during early development.
“this activity is quickly replaced by synapse-driven network events in which interneurons play a key role via depolarizing actions of GABA on PCs during early development”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ C. The Preoptic Area
Overexpression of Fezf2 in utero produces ectopic subcerebral principal cells below the white matter that preferentially attract PV- and SST-expressing interneurons, but not subtypes primarily found in superficial layers.
“overexpression of Fezf2 in utero produced ectopic subcerebral PCs below the white matter that preferentially attracted PV- and SST-expressing interneurons, but not subtypes primarily found in the superficial layers”
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- Premisecitation§ C. The Preoptic Area
In both the hippocampus and neocortex, the earliest activity occurs in the absence of synaptic connections in the form of spontaneous calcium plateaus, which are mediated by voltage-gated calcium channels and coordinated among cells by gap junction coupling.
“In both the hippocampus and neocortex, the earliest activity occurs in the absence of synaptic connections in the form of spontaneous calcium plateaus, which are mediated by voltage-gated calcium channels and coordinated among cells by gap junction coupling”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisecitation§ C. The Preoptic Area
MGE-derived interneurons laminate in the cortex according to birth order in the same inside-out manner as principal cells: early born cells migrate deeper than those born later.
“MGE-derived interneurons laminate in the cortex according to birth order in the same inside-out manner as PCs: early born cells migrate deeper than those born later”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ C. The Preoptic Area
When principal cells are induced to take on a subcerebral projection identity via Fezf2 overexpression, the number of synapses they receive from local PVBCs increases.
“when PCs are induced to take on a subcerebral projection identity via Fezf2 overexpression, the number of synapses they receive from local PVBCs increases”
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- Interpretationreasoning§ C. The Preoptic Area
Coordination between intrinsic cell identity and extrinsic cues found locally in the cortex is necessary to guide interneuron migration.
“This suggests that coordination between intrinsic cell identity and extrinsic cues found locally in the cortex is necessary to guide interneuron migration.”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
Structures throughout the entire developing nervous system generate network activity intrinsically before the arrival of mature external sensory stimuli.
“structures throughout the entire developing nervous system generate network activity intrinsically before the arrival of mature external sensory stimuli”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisenone given§ C. The Preoptic Area
The formation of neural circuits is crucially dependent on activity to trigger early plasticity mechanisms.
“the formation of neural circuits is crucially dependent on activity to trigger early plasticity mechanisms”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
MGE-derived interneurons may play a more prominent role in GDP generation than CGE-derived interneurons.
“those derived from the MGE may play a more prominent role than those from the CGE”
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- Premisecitation§ C. The Preoptic Area
Interneurons demonstrate AMPAR-mediated synaptic currents by the first postnatal day.
“interneurons demonstrate AMPAR-mediated synaptic currents by the first postnatal day”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ C. The Preoptic Area
GABA acts initially as an excitatory neurotransmitter to drive network activity important for synaptogenesis and circuit formation.
“GABA acts initially as an excitatory neurotransmitter to drive network activity important for synaptogenesis and circuit formation.”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
In CA1 of the hippocampus, optogenetic silencing of MGE-derived interneurons reduces the frequency of spontaneous GDPs to a greater extent than silencing those from the CGE.
“In CA1 of the hippocampus, optogenetic silencing of MGE-derived interneurons reduces the frequency of spontaneous GDPs to a greater extent than silencing those from the CGE”
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- Premisecitation§ C. The Preoptic Area
Knockdown of NKCC1 stunted the arrival of AMPAR-mediated synaptic events as well as dendritic branching and spine density in principal cells.
“Wang et al. (1185) knocked down NKCC1 (which accumulates Cl−) using RNA interference to render GABA hyperpolarizing/shunting throughout development, and this stunted the arrival of AMPAR-mediated synaptic events as well as dendritic branching and spine density in PCs.”
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- Interpretationreasoning§ C. The Preoptic Area
During the first postnatal week, interneurons and principal cells form excitatory circuits that precede those between principal cells.
“Thus, during the first postnatal week, interneurons and PCs form excitatory circuits that precede those between PCs.”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
In both the neocortex and hippocampus, network oscillations dependent on glutamatergic and GABAergic synapses emerge near the middle of the first postnatal week.
“In both the neocortex and hippocampus, network oscillations dependent on glutamatergic and GABAergic synapses emerge near the middle of the first postnatal week”
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- cites [27] source
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- cites [88] source
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- cites [241] source
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- cites [423] source
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- cites [663] source
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- Premisecitation§ C. The Preoptic Area
CGE-derived interneurons play a role in GDP generation.
“CGE-derived interneurons certainly play a role in GDP generation.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
In both the hippocampus and neocortex, these in vitro neonatal network activity patterns have in vivo counterparts.
“in both the hippocampus and neocortex, these in vitro neonatal network activity patterns have in vivo counterparts”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
GABAergic synapses between immature interneurons in the hippocampus remain hyperpolarizing and shunting throughout development.
“GABAergic synapses between immature interneurons in the hippocampus remain hyperpolarizing and shunting throughout development”
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- Premisecitation§ C. The Preoptic Area
In both the neocortex and hippocampus, interneurons send and receive the earliest synaptic connections.
“In both the neocortex and hippocampus, interneurons send and receive the earliest synaptic connections, with important consequences for circuit assembly.”
Quote in the paperSubstantial claim - Interpretationcitation§ C. The Preoptic Area
GABAergic depolarization and NMDARs act in concert to promote principal cell synaptogenesis.
“Thus they functionally demonstrated that GABAergic depolarization and NMDARs act in concert to promote PC synaptogenesis”
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- Premisecitation§ C. The Preoptic Area
At least in the hippocampus, MGE-derived interneurons appear to be morphologically and synaptically more mature than those from the CGE during the first postnatal week.
“At least in the hippocampus, MGE-derived interneurons appear to be morphologically and synaptically more mature than those from the CGE during the first postnatal week”
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- Premisecitation§ C. The Preoptic Area
At least in the hippocampus, interneurons demonstrate functional GABAergic synapses very early during postnatal development.
“at least in the hippocampus, interneurons demonstrate functional GABAergic synapses very early during postnatal development”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Coexpressing a mutant NMDAR less susceptible to Mg2+ block rescued the development of AMPAR-mediated synaptic transmission.
“Wang et al. (1185) rescued the development of AMPAR-mediated synaptic transmission by coexpressing a mutant NMDAR that is less susceptible to Mg2+ block.”
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- Interpretationreasoning§ C. The Preoptic Area
As interneurons become inhibitory, they sculpt early circuits by supporting competition among nascent synapses.
“Thus, as interneurons become inhibitory, they sculpt early circuits by supporting competition among nascent synapses.”
Quote in the paperSubstantial claim - Interpretationreasoning§ C. The Preoptic Area
PNNs are an important candidate mechanism for the establishment of mature inhibitory circuits and plasticity rules.
“Thus PNNs are an important candidate mechanism for the establishment of mature inhibitory circuits and plasticity rules.”
Quote in the paperSubstantial claim - Premisecitation§ C. The Preoptic Area
BDNF release is stimulated by calcium entry through VDCCs activated by early depolarizing GABA.
“BDNF promotes inhibitory synapse development by reducing GABAAR endocytosis, and its release is stimulated by calcium entry through voltage-dependent Ca2+ channels (VDCCs) activated by early depolarizing GABA (919).”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
Recent work suggests that the projection target of PCs informs connectivity rules with local interneurons.
“Importantly, PCs can be segregated into distinct subtypes based on the projection target of their long-range axons (313, 432, 466), and recent work suggests this informs connectivity rules with local interneurons (607).”
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- Premisecitation§ C. The Preoptic Area
As neurons mature, the reversal potential for chloride becomes shunting/hyperpolarizing, leading to inhibitory GABAergic transmission.
“As neurons mature, the reversal potential for chloride becomes shunting/hyperpolarizing, leading to inhibitory GABAergic transmission”
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- Premisecitation§ C. The Preoptic Area
Acceleration of interneuron circuit development by overexpressing BDNF closes the critical period early.
“Conversely, acceleration of interneuron circuit development by overexpressing brain-derived neurotrophic factor (BDNF) closes the critical period early (463, 507).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
The diversity of interneuron subtypes leads to sophisticated control of synaptic integration along the somatodendritic axis of PCs, as they differentially target distinct subcompartments.
“The diversity of interneuron subtypes leads to sophisticated control of synaptic integration along the somatodendritic axis of PCs, as they differentially target distinct subcompartments (see sect. VIID) (586).”
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- Premisecitation§ C. The Preoptic Area
PNNs facilitate the capture and uptake of the transcription factor Otx2.
“PNNs also facilitate the capture and uptake of the transcription factor Otx2, which in turn promotes PVBC maturation as well as further PNN development (100, 173, 912, 1063).”
Quote in the paperSubstantial claim0 of 4 sources checked - Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
PCs can be segregated into distinct subtypes based on the projection target of their long-range axons.
“Importantly, PCs can be segregated into distinct subtypes based on the projection target of their long-range axons (313, 432, 466), and recent work suggests this informs connectivity rules with local interneurons (607).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ C. The Preoptic Area
BDNF promotes inhibitory synapse development by reducing GABAAR endocytosis.
“BDNF promotes inhibitory synapse development by reducing GABAAR endocytosis, and its release is stimulated by calcium entry through voltage-dependent Ca2+ channels (VDCCs) activated by early depolarizing GABA (919).”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
In the neocortex, PVBCs are more likely to innervate PCs that project to subcerebral targets than those that project within the telencephalon.
“In the neocortex, PVBCs are more likely to innervate PCs that project to subcerebral targets (e.g, brain stem and spinal cord) than those that project within the telencephalon (e.g., callosal) (650, 1249) (FIGURE 8B).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
Closure of the critical period coincides with the establishment of perineuronal nets (PNNs).
“Interestingly, closure of the critical period coincides with the establishment of perineuronal nets (PNNs), which are structures of the extracellular matrix that form around PVBCs and stabilize synapses (for reviews, see Refs. 1039, 1183).”
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In transgenic mice with disrupted GABA synthesis at synaptic terminals, the critical period for MD sensitivity fails to open unless GABA agonists are applied.
“In transgenic mice with disrupted GABA synthesis at synaptic terminals, the critical period for MD sensitivity fails to open unless GABA agonists are applied (308, 482).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. The Preoptic Area
A subset of hub cells born early during embryonic development projects a long-range axon outside of the hippocampus via the fimbria.
“a subset of hub cells born early during embryonic development also projects a long-range axon outside of the hippocampus via the fimbria”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
In CA1 of the hippocampus, PVBCs evoke larger IPSCs in PCs that project to the amygdala than those that project to the prefrontal cortex.
“Finally, in CA1 of the hippocampus, PVBCs evoke larger IPSCs in PCs that project to the amygdala than those that project to the prefrontal cortex; conversely, PVBCs are more likely to be innervated by and receive the largest excitatory drive from prefrontal cortex projecting PCs (656) (FIGURE 8E).”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
A similar connectivity rule exists for SST-containing Martinotti cells in deep cortical layers, as they form circuits preferentially with neighboring subcerebral projecting PCs.
“A similar connectivity rule exists for SST-containing Martinotti cells in deep cortical layers, as they form circuits preferentially with neighboring subcerebral projecting PCs (647, 1015) (FIGURE 8C).”
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Maturation of inhibitory circuits, in particular mediated by PVBCs, is necessary for the expression of early competitive plasticity.
“the maturation of inhibitory circuits, in particular mediated by PVBCs, is necessary for the expression of this early competitive plasticity”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
Multiple studies strongly suggest that subtype specific microcircuits indeed exist, even among PVBCs.
“However, multiple studies have challenged this view and strongly suggest that subtype specific microcircuits indeed exist, even among PVBCs (650, 656, 1230, 1252).”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationcitation§ C. The Preoptic Area
Onset and closure of critical periods depend on different threshold levels of inhibition achieved during postnatal development.
“The onset and closure of critical periods appears to depend on different threshold levels of inhibition that are achieved during postnatal development (1045).”
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- Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
Some interneuron subtypes, such as PVBCs and NGFCs, demonstrate very high rates of connectivity to PCs, with connection probabilities in paired recordings in the range of ~50-90%.
“Some subtypes, such as PVBCs and NGFCs, demonstrate very high rates of connectivity to PCs: connection probabilities in paired recordings are in the range of ~50–90% (204, 331, 876, 880).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on Subtype
In the hippocampus, PVBCs evoke larger amplitude IPSCs in PCs located near s.o. than those near s.r. (deep vs. superficial).
“Furthermore, in the hippocampus, PVBCs evoke larger amplitude IPSCs in PCs located near s.o. than those near s.r. (i.e., deep vs. superficial) (656) (FIGURE 8A).”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
With the use of a loose cell-attached configuration, an accurate measure of Vm can be established by exploiting the K+ reversal potential (EK+).
“With the use of a loose cell-attached configuration, an accurate measure of Vm can be established by exploiting the K+ reversal potential (EK+) (359, 1029, 1168).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
Using whole cell recording techniques, electrodes filled with either a high Cl− solution or gluconate-containing solution resulted in Vm measurements that were ~15 mV more depolarized.
“In contrast, using whole cell recording techniques, the same authors found that electrodes filled with either a high Cl− solution or gluconate-containing solution resulted in Vm measurements that were ~15mV more depolarized.”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
PV-containing cells (PVBCs, BiCs, AACs) and virtually all CGE-derived cell types (CCK-containing, long range projecting, VIP-containing) have the most depolarized resting potentials (approximately −55 to −60 mV).
“Cells of the neurogliaform family (NGFC, IvC) typically possess the most hyperpolarized Vm (mean −70 mV, cluster 3 in TABLE 1), whereas PV-containing cells (PVBCs, BiCs, AACs) and virtually all CGE-derived cell types (CCK-containing, long range projecting, VIP-containing) have the most depolarized resting potentials (approximately −55 to −60 mV).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Single-cell RT-PCR revealed that the fast delayed rectifier and the A-type current components in O-LM cells were mediated by homomeric Kv3.2 and Kv4.3 channels, respectively.
“Single-cell reverse transcription polymerase chain reaction (RT-PCR) revealed that the fast delayed rectifier and the A-type current components were mediated by homomeric Kv3.2 and Kv4.3 channels, respectively (678).”
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- Premiseown data§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
Despite possessing varied resting potentials, virtually all cells had similar action potential thresholds close to −35 mV (range −32 to −38 mV).
“Despite possessing varied resting potentials, virtually all cells had similar action potential thresholds close to −35mV (range −32 to −38 mV) (TABLE 1).”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
The loose cell-attached approach revealed that resting potentials of specific cell types were often more hyperpolarized than original estimates provided by the whole cell recording configuration.
“This approach revealed that resting potentials of specific cell types were often more hyperpolarized than original estimates provided by the whole cell recording configuration.”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
Cells of the neurogliaform family (NGFC, IvC) typically possess the most hyperpolarized Vm (mean −70 mV, cluster 3 in TABLE 1).
“Cells of the neurogliaform family (NGFC, IvC) typically possess the most hyperpolarized Vm (mean −70 mV, cluster 3 in TABLE 1), whereas PV-containing cells (PVBCs, BiCs, AACs) and virtually all CGE-derived cell types (CCK-containing, long range projecting, VIP-containing) have the most depolarized resting potentials (approximately −55 to −60 mV).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Few channels expressed in recombinant systems perfectly matched the biophysical properties of native channels.
“This optimism was short lived as it became apparent that few channels expressed in recombinant systems perfectly matched the biophysical properties of native channels (967).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Early attempts to match expression patterns of cloned channel transcripts with biophysical properties measured by whole cell recording in in vitro slices yielded some modest successes, particularly with channels formed by the Kv3 family.
“Early attempts to match expression patterns of recent cloned channel transcripts with biophysical properties measured by whole cell recording techniques in in vitro slices did, however, yield some modest successes, particularly with channels formed by the Kv3 family of voltage-gated potassium channels (967) as discussed below.”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
The complement of both voltage- and ligand-gated channels expressed on hippocampal inhibitory interneurons differs markedly from those expressed on their glutamatergic principal cell counterparts.
“The last two decades have strengthened early observations suggesting that the complement of both voltage- and ligand-gated channels expressed on hippocampal inhibitory interneurons differs markedly from those expressed on their glutamatergic principal cell counterparts (502, 641, 770).”
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A second approach that exploits the known reversal potential of NMDAR-gated single-channel currents has also been effective in accurately determining resting and threshold properties of cells.
“A second, similar approach, that exploits the known reversal potential of NMDAR-gated single-channel currents, has also been effective in accurately determining resting and threshold properties of cells (90, 943, 1148).”
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SST-containing cells (e.g., O-LM cells) have resting potentials intermediate to all other cells (Vm = −65 mV).
“SST-containing cells (e.g., O-LM cells) have resting potentials intermediate to all other cells (Vm = −65 mV).”
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- Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
Early electrophysiological studies using sharp microelectrode recording demonstrated that resting conductances and physiological firing patterns of inhibitory interneurons deviated markedly from their excitatory cell counterparts.
“Early electrophysiological studies of inhibitory interneurons using sharp microelectrode recording techniques were quick to demonstrate that the resting conductances and physiological firing patterns of inhibitory interneurons deviated markedly from their excitatory cell counterparts (567, 623, 624).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONS
In interneurons of the CA1 s.r., the loose cell-attached approach yielded Vm values that ranged from −59 to −93 mV (mean −74 mV).
“For example, in interneurons of the CA1 s.r., this approach yielded Vm values that ranged from −59 to −93 mV (mean −74 mV) (cf. with CA1 pyramidal cells Vm = −84mV; Ref. 359).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Early recordings from interneurons located within the s.o. and s.r. indicated that both transient A-type and numerous sustained delayed rectifier currents were common to virtually all interneurons.
“Early recordings from interneurons located within the s.o. and s.r. indicated that both transient “A-type” and numerous sustained “delayed rectifier” currents were common to virtually all interneurons (202, 678, 756, 1268, 1269).”
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Delayed rectifier channels assembled from Kv3 subunits are instrumental components in conferring high-frequency action potential firing in numerous hippocampal and cortical interneuron subtypes.
“Delayed rectifier channels assembled from Kv3 subunits are instrumental components in conferring high-frequency action potential firing in numerous hippocampal and cortical interneuron subtypes (304, 967, 1187).”
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These currents contributed 57, 25, and 19% to the total macroscopic current in O-LM cells.
“These currents contributed 57, 25, and 19% to the total macroscopic current.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Similar electrophysiological recordings from PVBCs revealed that macroscopic currents were dominated (~58%) by a fast non-inactivating delayed rectifier current component sensitive to low concentrations of 4-AP and TEA.
“Similar electrophysiological recordings from PVBCs revealed that macroscopic currents were dominated (~58%) by a fast non-inactivating delayed rectifier current component sensitive to low concentrations of 4-AP and TEA (IC50 = <100 mM), similar (but not identical) to that observed in dendrite targeting SST-containing interneurons (FIGURE 10 and TABLE 2) (678).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Single-cell RT-PCR revealed a high prevalence of Kv3.1 and Kv3.2 in all PVBCs with a lower abundance of Kv4.2 and Kv4.3 transcripts.
“Single-cell RT-PCR revealed a high prevalence of Kv3.1 and Kv3.2 in all PVBCs with a lower abundance of Kv4.2 and Kv4.3 transcripts.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Kv3 expression is highest in dendrites of cells that typically possess low dendritic Na+ channel densities.
“Kv3 expression is highest in dendrites of cells that typically possess low dendritic Na+ channel densities (502, 504).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
During the first two to three postnatal weeks of life, action potential duration, propagation time, and duration of the transmitter release period decrease by ~50% as a result of the concurrent functional maturation of cell morphology, voltage-gated Na+ and K+ currents, as well as refinement of the presynaptic release machinery.
“Consequently, during the first two to three postnatal weeks of life, action potential duration, propagation time, and duration of the transmitter release period decrease by ~50% as a result of the concurrent functional maturation of cell morphology, voltage-gated Na+ and K+ currents, as well as refinement of the presynaptic release machinery (277, 502).”
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Brief repetitive stimulation of Schaffer collateral inputs to PV-containing cells results in a novel form of long-term intrinsic plasticity.
“Finally, brief repetitive stimulation of Schaffer collateral inputs to PV-containing cells results in a novel form of long-term intrinsic plasticity (160).”
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- Interpretationreasoning§ C. Voltage-Gated K+ Conductances
These subtle differences likely set the upper firing frequency of O-LM cells to be lower than PVBCs.
“These subtle differences likely set the upper firing frequency of O-LM cells to be lower than PVBCs.”
Quote in the paperSubstantial claim - Premisecitation§ C. Voltage-Gated K+ Conductances
Action potential propagation and transmitter release components cannot support the rapid throughput typically observed in mature cells.
“In addition, action potential propagation and transmitter release components cannot support the rapid throughput typically observed in mature cells.”
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Kv3.2 subunits, but not Kv3.1 subunits, possess a consensus sequence for protein kinase A (PKA) phosphorylation.
“Kv3.2 subunits, but not Kv3.1 subunits, possess a consensus sequence for protein kinase A (PKA) phosphorylation (803, 965).”
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Gamma oscillations in the young hippocampus are poorly organized in part due to the immature state of PV-containing interneurons.
“Gamma oscillations in the young hippocampus are poorly organized in part due to the immature state of PV-containing interneurons.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Goldberg et al. observed that the slow inactivation of Kv1 containing channels in PV-containing cells of the barrel cortex causes a shift in the threshold for action potential initiation.
“Goldberg et al. (415) observed that the slow inactivation of Kv1 containing channels in PV-containing cells of the barrel cortex causes a shift in the threshold for action potential initiation.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Postnatal upregulation of Kv3 containing currents in PV-containing cells is part of a coordinated sequence of events that tune PV cells for their ultimate participation in gamma oscillogenesis.
“Postnatal upregulation of Kv3 containing currents in PV-containing cells is part of a coordinated sequence of events that tune PV cells for their ultimate participation in gamma oscillogenesis (277, 287, 1098) (see sect. XV).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
A comparison of data from two publications from Peter Jonas' laboratory reveals important quantitative differences between the rapidly activating sustained K+ currents in O-LM and PVBCs.
“A comparison of the data from two publications from Peter Jonas’ laboratory (678, 756), who used identical recording techniques in O-LM and PVBCs, reveals important quantitative differences between the rapidly activating sustained K+ currents in the two cell types (TABLE 2).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Kv3.1 subunits have 11 protein kinase C (PKC) and 10 casein kinase sites.
“Despite lacking a PKA phosphorylation site, Kv3.1 subunits have 11 protein kinase C (PKC) and 10 casein kinase sites (1166), suggesting that the phosphorylated state of both Kv3.1 and Kv3.2 could have a major impact on the firing properties of a number of interneuron populations.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Compared with the axon initial segments of principal cells, Kv1.1 and Kv1.2 are expressed at a much higher density.
“When compared with the axon initial segments of principal cells, Kv1.1 and Kv1.2 are expressed at a much higher density (695), suggesting that they may play a role in establishing an increased threshold for action potential initiation in PV-containing cells.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In hippocampus, both Kv3.1 and Kv3.2 protein expression are developmentally upregulated between PN7 and PN21.
“In hippocampus, both Kv3.1 and Kv3.2 protein expression are developmentally upregulated between PN7 and PN21 (287, 1098).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Kv1.1 likely functions to permit responses primarily to large events that can temporally exceed its rate of activation.
“Moreover, Kv1.1 likely functions to permit responses primarily to large events that can temporally exceed its rate of activation.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Outside-out patch-clamp recordings from different portions of the somatodendritic domain revealed a reasonably uniform high density of Na+ channels regardless of the compartment in O-LM cells.
“Outside-out patch-clamp recordings from different portions of the somatodendritic domain revealed a reasonably uniform high density of Na+ channels regardless of the compartment (757).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
High-resolution immunohistochemical analyses reveal marked heterogeneity of Ca2+ channel subunit expression throughout mouse hippocampal interneuron subtypes.
“High-resolution immunohistochemical analyses of Ca2+ channel subunit expression reveals a marked heterogeneity throughout mouse hippocampal interneuron subtypes (1174).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Using a small interfering RNA knock down approach, Bourdeau et al. implicated Kv4.3 containing channels in the generation of these subthreshold membrane potential oscillations.
“Using a small interfering RNA knock down approach, Bourdeau et al. (119) implicated Kv4.3 containing channels in the generation of these subthreshold membrane potential oscillations, suggesting that significant A-type current can be active at potentials close to rest and have roles in physiological processes other than action potential repolarization.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
The molecular identities of Na+ channels in interneurons suggest that at least in PVBCs the vast majority of Na+ channels are formed by Nav1.1 and Nav1.6 subunits with a lesser contribution from Nav1.2, Nav1.4, and Nav1.7.
“The molecular identities of Na+ channels in interneurons suggest that at least in PVBCs the vast majority of Na+ channels are formed by Nav1.1 and Nav1.6 subunits with a lesser contribution from Nav1.2, Nav1.4, and Nav1.7 (502, 695, 857, 852).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
The earliest study of Na+ conductances in fast spiking interneurons revealed significant differences between interneurons and their principal cell counterparts.
“The earliest study of Na+ conductances in fast spiking interneurons revealed significant differences between interneurons and their principal cell counterparts (755).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Application of the muscarinic acetylcholine receptor (mAChR) agonist carbachol to in vitro hippocampal slices generates theta frequency subthreshold membrane potential oscillations in inhibitory interneurons.
“Application of the muscarinic acetylcholine receptor (mAChR) agonist carbachol to in vitro hippocampal slices generates theta frequency subthreshold membrane potential oscillations in inhibitory interneurons (191) that are generated by the interplay of voltage-dependent K+ (IA, IKfast, IKslow, and ID) and persistent Na+ conductances (191).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
The midpoint for Na+ channel activation was observed at more negative potentials in the dendrites compared with somas in O-LM cells.
“Of interest, the midpoint for Na+ channel activation was observed at more negative potentials in the dendrites compared with somas.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [757] source
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Janssen et al. directly demonstrated that application of exogenous neuregulin (NRG1) reduces the excitability of Erb4-expressing interneurons (of which PV-containing cells are a subset) in primary culture by raising action potential threshold and decreasing Na+ channel activity by an as yet unknown mechanism.
“While the data regarding neuromodulation of Na+ channels in interneurons are sparse, Janssen et al. (528) directly demonstrated that application of exogenous neuregulin (NRG1) reduces the excitability of Erb4-expressing interneurons (of which PV-containing cells are a subset) in primary culture by raising action potential threshold and decreasing Na+ channel activity by an as yet unknown mechanism”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
These oscillations are generated by the interplay of voltage-dependent K+ (IA, IKfast, IKslow, and ID) and persistent Na+ conductances.
“Application of the muscarinic acetylcholine receptor (mAChR) agonist carbachol to in vitro hippocampal slices generates theta frequency subthreshold membrane potential oscillations in inhibitory interneurons (191) that are generated by the interplay of voltage-dependent K+ (IA, IKfast, IKslow, and ID) and persistent Na+ conductances (191).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
The time constant for recovery from inactivation was identical at both locations in O-LM cells.
“However, the time constant for recovery from inactivation was identical at both locations (757).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Transient cerebral ischemia impacts Na+ channel activation and surface expression in PV-containing interneurons rendering cells less excitable.
“Transient cerebral ischemia also impacts Na+ channel activation and surface expression in PV-containing interneurons rendering cells less excitable (1265).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Cav2.1 and Cav3.1 subunits are uniformly expressed in almost all interneuron subtypes.
“Cav2.1 (responsible for P/Q-type VDCCs) and Cav3.1 (T-type VDCCs) subunits are uniformly expressed in almost all interneuron subtypes.”
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- Interpretationreasoning§ C. Voltage-Gated K+ Conductances
This negatively shifted activation range undoubtedly has a major role to play in lowering the threshold for spike initiation in SST-containing cells whose axons often emerge from portions of the dendritic tree.
“This negatively shifted activation range undoubtedly has a major role to play in lowering the threshold for spike initiation in SST-containing cells whose axons often emerge from portions of the dendritic tree.”
Quote in the paperNot a substantial claim - Premisecitation§ C. Voltage-Gated K+ Conductances
Both Kv4.1 and Kv4.2 channels are largely absent from hippocampal interneurons.
“Both Kv4.1 and Kv4.2 channels are largely absent from hippocampal interneurons (944).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Kv4.3 is expressed in only a small percentage of PV-containing cells.
“In contrast, Kv4.3 is expressed in only a small percentage of PV-containing cells (119).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In hippocampus, Kv4.3 expression is highest in the somatodendritic compartments of CCK-containing and CB-containing interneurons located in both s.r. and s.l.m. as well as SST-containing interneurons in s.p. and s.o.
“In hippocampus, Kv4.3 expression is highest in the somatodendritc compartments of CCK-containing, and CB-containing interneurons located in both s.r. and s.l.m. as well as SST-containing interneurons in s.p. and s.o. (119, 678, 782).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Unlike PV-containing interneurons, SST-containing cells, particularly O-LM cells, have a comparatively high density of Na+ channels on their somatodendritic axis.
“Unlike PV-containing interneurons, SST-containing cells, particularly O-LM cells, have a comparatively high density of Na+ channels on their somatodendritic axis.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Calculations have suggested that 99% of PVBC Na+ channels are contained within the axonal compartment.
“Calculations have suggested that 99% of PVBC Na+ channels are contained within the axonal compartment (503).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
The greatest differences occurred in their steady-state inactivation properties, which were steeper and shifted to more positive voltages in PVBCs.
“However, the greatest differences occurred in their steady-state inactivation properties, which were steeper and shifted to more positive voltages in PVBCs (755).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Dendritic L-type VDCCs are implicated in Hebbian long-term potentiation at excitatory synapses onto interneurons.
“Dendritic L-type VDCCs are implicated in Hebbian long-term potentiation (LTP) at excitatory synapses onto interneurons (see sect. VIB) (1110, 1112), and high-frequency synaptic activity of mGluR5 induces a selective and compartmentalized potentiation of L-type channels by a PKC-dependent mechanism and release of Ca2+ from ryanodine-sensitive intracellular stores (1111).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Cav2.3 is uniformly expressed in all interneurons except PV-containing and CR-containing cells, where expression is much lower.
“Cav2.3 (R-type VDCCs) is also uniformly expressed in all interneurons except PV-containing and CR-containing where expression is much lower (1174).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Cav3 (T-type) channels have also been identified at presynaptic sites on PV-containing axons.
“In addition to HVA channels, Cav3 (T-type) channels have also been identified at presynaptic sites on PV-containing axons (1093).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
During trains of activity, dendrites of low-threshold spiking interneurons behave as a single nonlinear compartment generating global Ca2+ elevation across the entire dendritic tree.
“During trains of activity, the dendrites of low-threshold spiking interneurons behave as a single nonlinear compartment generating global Ca2+ elevation across the entire dendritic tree (416).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In situ hybridization suggests the majority of Ih channels in inhibitory neurons are formed from HCN1 and HCN2 subunits with a smaller contribution of HCN4 subunits.
“In situ hybridization analysis suggests that the majority of Ih channels in inhibitory neurons are formed from HCN1 and HCN2 subunits with a smaller contribution of HCN4 subunits (976).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Cav1.3 expression is highest in PV-containing and SST-containing interneurons.
“Cav1.3 expression is highest in PV-containing and SST-containing interneurons.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Ca2+ imaging studies first showed functional dendritic VDCCs mediate Ca2+ influx during synaptic depolarizations and back-propagating action potentials in numerous interneuron subtypes.
“Ca2+ imaging studies were first to show the presence of functional dendritic VDCCs that mediate Ca2+ influx during synaptic depolarizations and back-propagating action potentials in numerous interneuron subtypes (416, 418, 545, 961).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
L-type VDCC subunits Cav1.2 and Cav1.3 colocalize to CR-containing interneurons.
“The L-type VDCC subunits, Cav1.2 and Cav1.3, colocalize to CR-containing interneurons, while Cav1.3 expression is highest in PV-containing and SST-containing interneurons.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Currents through L-type channels facilitate CREB phosphorylation important for excitatory transcription coupling in PV-containing cells.
“Moreover, currents through L-type channels facilitate CREB phosphorylation important for excitatory transcription coupling in PV-containing cells (214).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In hippocampus, imaging of Ca2+ transients triggered by back-propagating action potentials in SST-containing O-LM cells revealed contributions of T, L, N, and P/Q channel types.
“In hippocampus, imaging of Ca2+ transients triggered by back-propagating action potentials in SST-containing O-LM cells revealed contributions of T, L, N, and P/Q channel types (1111).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In SST-containing low threshold spiking cortical interneurons, dendritic T-type channels trigger low-threshold spikes and subsequent recruitment of other Ca2+ channel types including R- and L-type channels.
“In these cells dendritic T-type channels trigger low-threshold spikes and subsequent recruitment of other Ca2+ channel types including R- and L-type channels.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Cav2.2 is expressed in all interneurons except CB-containing cells.
“Cav2.2 (N-type VDCCs) is expressed in all interneurons with the exception of CB-containing cells.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Application of BDNF decreases the firing frequency and input resistance of PV-containing cells by a mechanism involving a TrkB-mediated increase of IM.
“Application of BDNF decreases the firing frequency and input resistance of PV-containing cells by a mechanism involving a TrkB-mediated increase of IM.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Blockade of IM increases spontaneous firing frequency by reducing the interspike interval without impacting action potential half-width.
“Blockade of IM increases spontaneous firing frequency by reducing the interspike interval without impacting action potential half-width.”
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- Premisecitation§ I. TASK Channels
Single-cell RT-PCR and immunohistochemistry have demonstrated that TASK3 is expressed in about 50% of GAD67-positive interneurons.
“Single-cell RT-PCR and immunohistochemistry have demonstrated that TASK3 is expressed in ~50% of GAD67-positive interneurons.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
BDNF strongly modulates the firing of PV-containing cells via an action on IM availability.
“Finally, BDNF strongly modulates the firing of PV-containing cells via an action on IM availability (837).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Using standard depolarizing test pulses, IM contributes about 15% of the total outward current activated at +40 mV.
“Using standard depolarizing test pulses, IM contributes ~15% of the total outward current activated at +40 mV.”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In mouse models of electrographic seizures, termination of the electrographic event depends on the activity of ASIC1a channels.
“In mouse models of electrographic seizures (kainate acid lesioning, PTZ, and reduced extracellular Mg2+), termination of the electrographic event depends on the activity of ASIC1a channels (1277).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Immunohistochemistry has shown Kv7 channel expression on the soma and dendritic compartments of PV-containing and SST-containing interneuron populations.
“Immunohistochemistry has shown Kv7 channel expression on the soma and dendritic compartments of PV-containing and SST-containing interneuron populations (222, 645).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Rapid acidification of the extracellular environment triggers activation of an inward ASIC channel-mediated current at −60 mV in O-LM and PVBCs, as well as unidentified interneurons of s.r. and s.l.m.
“Rapid acidification of the extracellular environment triggers activation of an inward ASIC channel-mediated current (at −60 mV) in O-LM and PVBCs (1196), as well as unidentified interneurons of s.r. and s.l.m. (113, 1102).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. Voltage-Gated K+ Conductances
Block of Ih decreases spontaneous action potential frequency by prolonging the interspike trajectory.
“Block of Ih also decreases spontaneous action potential frequency by prolonging the interspike trajectory (718).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
Selective block of ASIC1a on inhibitory neuron presynaptic terminals reduces electrographic seizure activity in low Mg2+ and kainate-induced models by a mechanism involving presynaptic ASIC channel modulation of inhibitory tone.
“However, selective block of ASIC1a on inhibitory neuron presynaptic terminals actually reduces electrographic seizure activity in low Mg2+ and kainate-induced models of seizures by a mechanism involving presynaptic ASIC channel modulation of inhibitory tone (1102), suggesting that interneuron”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In side-by-side recordings, ASIC currents were sixfold greater in O-LM cells (current density 0.75 pA/μm2) compared with PVBCs (0.12 pA/μm2, a density similar to that observed in principal cells).
“In side-by-side recordings, ASIC currents were sixfold greater in O-LM cells (current density 0.75 pA/μm2) compared with PVBCs (0.12 pA/μm2, a density similar to that observed in principal cells).”
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- Premisecitation§ C. Voltage-Gated K+ Conductances
In the presence of mAChR agonists, SST-containing O-LM cells and CCKBCs exhibit an M1/M3-receptor dependent acceleration of action potential firing frequency concomitant with the emergence of a prominent afterdepolarization.
“In the presence of mAChR agonists, SST-containing O-LM cells and CCKBCs exhibit an M1/M3-receptor dependent acceleration of action potential firing frequency concomitant with the emergence of a prominent afterdepolarization (ADP).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ I. TASK Channels
Combining both morphological and electrophysiological features revealed five cell clusters comprising PVBCs, HICAPs, total molecular layer cells, HIPPs, and molecular layer cells.
“Combining both morphological and electrophysiological features revealed five cell clusters comprising PVBCs (BC, cluster), HICAPs, total molecular layer cells, HIPPs, and molecular layer cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [499] source
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- Premisecitation§ I. TASK Channels
Both effects of acidification or alkalinization were blocked by bupivacaine, consistent with a role for TASK channels in establishing intrinsic resting parameters.
“Both of these effects were blocked by the anesthetic bupivacaine consistent with a role for TASK channels in establishing intrinsic resting parameters (1113).”
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- Premisecitation§ I. TASK Channels
Most excitatory synapses are made onto spine-free, smooth dendrites of inhibitory interneurons.
“Most excitatory synapses are made onto spine-free, smooth dendrites of inhibitory interneurons (1035) (see sect. V).”
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- Premisecitation§ I. TASK Channels
This compartmentalization of the synaptic signal resulted from the unique combination of the kinetics of the underlying Ca2+-permeable AMPARs and a fast extrusion mechanism provided by a proximally located low-affinity, high-capacity Na+/Ca2+ exchanger.
“This “compartmentalization” of the synaptic signal resulted from the unique combination of both the kinetics of the underlying Ca2+-permeable AMPARs and a fast extrusion mechanism provided by a proximally located low-affinity, high-capacity Na+/Ca2+ exchanger.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [417] source
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- Premisecitation§ I. TASK Channels
One landmark study highlighted an essential role for the Na+/Ca2+ exchanger in providing input specific dendritic compartmentalization of synaptic signaling in neocortical fast spiking interneurons.
“However, one landmark study highlighted an essential role for the Na+/Ca2+ exchanger in providing input specific dendritic compartmentalization of synaptic signaling in neocortical fast spiking interneurons (417).”
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- Premisecitation§ I. TASK Channels
With the exception of molecular layer cells, analysis of electrophysiological parameters alone was insufficient to clearly delineate interneuron subtypes.
“However, with the exception of molecular layer cells (ML, corresponding to MOPP cells and NGFCs) analysis of electrophysiological parameters alone were insufficient to clearly delineate interneuron subtypes, confirming our hypothesis that there is a continuum for sampled electrophysiological parameters that are often insufficient to permit fine grain definition of individual interneuron subtypes.”
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- Premisecitation§ I. TASK Channels
All nine identified cell types largely exhibit a continuum of intrinsic parameters.
“Close inspection of the electrophysiological properties of these cells, however, highlight few features that are distinct to one or few cell types, with only minor exceptions, and all nine identified cell types largely exhibit a continuum of intrinsic parameters.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [796] source
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- Interpretationcitation§ 1. PV-containing interneurons
This supercritical density of Na+ channels likely ensures failsafe and rapid action potential propagation.
“This “supercritical” density of Na+ channels likely ensures failsafe and rapid action potential propagation.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [503] source
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- Premisecitation§ I. TASK Channels
Blockade of the Na+/Ca2+ exchanger with benzamil increased the spatial spread of Ca2+ microdomains.
“Indeed, blockade of the Na+/Ca2+ exchanger with benzamil increased the spatial spread of Ca2+ microdomains (417).”
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- Premisecitation§ I. TASK Channels
The majority of CGE-derived interneurons that did not express reelin expressed VIP.
“The majority of CGE-derived interneurons that did not express reelin expressed VIP.”
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- Premisecitation§ I. TASK Channels
Goldberg and colleagues observed that synaptic input generated Ca2+ transients that were remarkably localized despite the absence of physical structures to limit Ca2+ spread.
“Surprisingly, they observed that synaptic input generated Ca2+ transients that were remarkably localized despite the absence of physical structures to limit the Ca2+ spread (417).”
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- Premisecitation§ 1. PV-containing interneurons
Hu and Jonas demonstrated that the dendrites and somas of PV cells possess a low density of Na+ channels (~1% of total).
“In a remarkable series of patch-clamp recordings, Hu and Jonas (503) demonstrated that the dendrites and somas of PV cells possess a low density of Na+ channels (~1% of total).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [503] source
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- Premisecitation§ I. TASK Channels
The third class of NPY-expressing cells are PVBCs with low input resistance, short membrane time constant, and high rheobase.
“3) PVBCs with low input resistance, short membrane time constant, and high rheobase comprised the third class of distinct NPY-containing interneurons.”
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- Premisecitation§ I. TASK Channels
The first class of NPY-expressing cells are nNOS-expressing NGFCs with a dense axonal plexus and a late-spiking phenotype.
“1) The first class are nNOS-expressing NGFCs with a dense axonal plexus and a late-spiking phenotype.”
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- Interpretationown data§ I. TASK Channels
The observation of no overlap of functional characteristics between MGE- versus CGE-derived cells within five of the six clusters suggests that cell origin has high discriminative power in the cluster analyses.
“The observation of no overlap of functional characteristics between MGE-versus CGE-derived cells within five of the six clusters suggests that the cell origin has high discriminative power in the cluster analyses (FIGURE 12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1138] source
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- Premisecitation§ I. TASK Channels
Acidification or alkalinization of the extracellular fluid impacts the input resistances and holding currents required to voltage-clamp at rest diverse populations of CA1 interneurons.
“Accordingly, acidification or alkalinization of the extracellular fluid impacts the input resistances and holding currents required to voltage-clamp at rest diverse populations of CA1 interneurons.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1113] source
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- Premisecitation§ 1. PV-containing interneurons
At distal locations the Na+ conductance density was reported as ~600 pS/μm2.
“At distal locations the Na+ conductance density was reported as ~600 pS/μm2.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [503] source
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- Premisecitation§ I. TASK Channels
Cluster analysis based on morphometric variables of 114 sampled cells revealed 5 distinct classes of interneurons each with distinct morphophysiological features.
“Cluster analysis based on morphometric variables of 114 sampled cells revealed 5 distinct classes of interneurons each with distinct morphophysiological features.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [499] source
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- Premisecitation§ 1. PV-containing interneurons
Na+ channel density progressively increases (~100-fold) with distance along the axon.
“The Na+ channel density progressively increases (~100-fold) with distance along the axon (FIGURE 10B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [503] source
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- Interpretationcitation§ I. TASK Channels
Taken together, two independent studies using morphological and physiological features of randomly selected neurons yield cell cluster identities with remarkable consistency across different hippocampal subfields.
“Taken together, these two independent studies using morphological and physiological features of randomly selected neurons yield cell cluster identities with remarkable consistency across different hippocampal subfields.”
Quote in the paperSubstantial claim0 of 2 sources checked - Premiseown data§ I. TASK Channels
Cluster 3 was the only group to comprise cells derived from both the MGE and CGE that were characterized as expressing NPY-mRNA and possessed a late spiking firing phenotype consistent with Ivy and NGFC populations.
“Cluster 3 was the only group to comprise cells derived from both the MGE and CGE that were characterized as expressing NPY-mRNA and possessed a late spiking firing phenotype consistent with Ivy and NGFC populations (TABLE 1).”
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- Premisecitation§ I. TASK Channels
Karagiannis et al. data analysis from 200 cells suggested three main populations of NPY-expressing cells.
“Their extensive data analysis from 200 cells suggested three main populations of NPY-expressing cells.”
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- Premisecitation§ I. TASK Channels
A data set from in excess of 140 cells resulted in identification of six robust cell clusters.
“This data set, obtained from in excess of 140 cells, resulted in identification of six robust cell clusters.”
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- Premisecitation§ 1. PV-containing interneurons
The release probability (Pr) at PV synapses is high (~0.6).
“The measured half duration of quantal release at these synapses is ~300 μs, and Pr is high (~0.6) (602).”
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- Premisecitation§ 2. CCK-containing cells
CCK cells fire action potentials with longer durations (>0.5 ms) than PV cells.
“In addition, CCK cells fire action potentials with longer durations (>0.5 ms), which lengthen upon repetitive activation during trains further contrasting with their PV cell counterparts (182).”
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- Interpretationreasoning§ 1. PV-containing interneurons
Through a combination of anatomical and molecular specializations, action potential initiation, propagation, and presynaptic invasion are tuned to ensure rapid and reliable neurotransmission to downstream targets.
“Thus, through a combination of anatomical and molecular specializations, action potential initiation, propagation, and presynaptic invasion are “tuned” to ensure rapid and reliable neurotransmission to downstream targets, consistent with a role for these cells in enforcing temporally precise feedforward/feedback-inhibitory control as well as the generation of coherent oscillations within cortical”
Quote in the paperSubstantial claim - Premisecitation§ 1. PV-containing interneurons
The short physical distance between the site of Ca2+ entry and the synaptic release machinery enforces a tight coupling between action potential invasion and neurotransmitter release with rapid and precise temporal dynamics.
“The short physical distance between the site of Ca2+ entry and the synaptic release machinery enforces a tight coupling between action potential invasion and neurotransmitter release with rapid and precise temporal dynamics (132, 477).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 1. PV-containing interneurons
Ca2+ entry through P/Q-type voltage-gated Ca2+ channels is tightly coupled to the exocytotic release machinery via formation of specialized nanodomains.
“Ca2+ entry through P/Q channels is tightly coupled to the exocytotic release machinery via formation of specialized “nanodomains” (296).”
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- Interpretationcitation§ 2. CCK-containing cells
Postsynaptic targets may influence synchronicity of release for certain CCK cell subtypes.
“However, Ali and Todorova (21) observed that the synchronicity ratio for CCK cells residing at the s.l.m.-s.r. border was larger for postsynaptic interneurons than CA1 pyramidal cells, suggesting that postsynaptic targets may influence synchronicity of release for certain CCK cell subtypes.”
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- Interpretationreasoning§ 1. PV-containing interneurons
The brevity of action potentials combined with rapid Ca2+ entry tightly coupled to release machinery ensures that neurotransmission from PVBCs to downstream targets proceeds with high efficiency.
“The brevity of action potentials combined with rapid Ca2+ entry that is tightly coupled to release machinery ensures that neurotransmission from PVBCs to their downstream targets will proceed with high efficiency.”
Quote in the paperSubstantial claim - Premisecitation§ 3. NGFCs
The axonal arborization of NGFCs has been calculated to approximate 140,000 μm in length, compared with ~46,000 μm for a typical PVBC.
“The axonal arborization has been calculated to approximate 140,000 μm in length, compared with ~46,000 μm for a typical PVBC.”
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- Premisecitation§ 1. PV-containing interneurons
Inhibitory strength from DG PVBC axons declines with distance to principal cell targets, presumably due to lower contact numbers.
“Inhibitory strength declined (presumably due to lower contact numbers) and signal duration was increased with distance (likely due to changes in postsynaptic GABAA receptor subunit composition) between the presynaptic cell and the downstream targets.”
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- Interpretationcitation§ 1. PV-containing interneurons
The Ca2+ binding properties of syt2 likely serve to minimize the time required between Ca2+ entry and the liberation of neurotransmitter.
“The Ca2+ binding properties of syt2 likely serve to minimize the time required between Ca2+ entry and the liberation of neurotransmitter (502).”
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- Interpretationcitation§ 2. CCK-containing cells
Separate Ca2+ sensors may underlie the two modes of release.
“Elimination of dominant presynaptic Ca2+ sensor synaptotagmin isoforms (Syt2 at the Calyx of Held or Syt1 at DG cell synapses) (576, 1066) selectively eliminates synchronous release revealing an increase in asynchronous release, suggesting that separate Ca2+ sensors may underlie the two modes of release.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ 1. PV-containing interneurons
The distance-scaling feature of PV-containing interneurons facilitates their ability to synchronize large principal cell populations during gamma frequency oscillations.
“Of particular interest, this distance-scaling feature appears to facilitate the ability of PV-containing interneurons to synchronize large principal cell populations during gamma frequency oscillations (1058).”
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- Premisecitation§ 3. NGFCs
NGFCs mediate a third form of GABAergic transmission intermediate between phasic and tonic signaling.
“Interestingly, NGFCs mediate a third form of GABAergic transmission intermediate between phasic and tonic signaling (165) (FIGURE 13C).”
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- Premisecitation§ 1. PV-containing interneurons
The measured half duration of quantal release at PV synapses is ~300 μs.
“The measured half duration of quantal release at these synapses is ~300 μs, and Pr is high (~0.6) (602).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [602] source
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- Premisecitation§ 2. CCK-containing cells
Ali and Todorova observed that the synchronicity ratio for CCK cells residing at the s.l.m.-s.r. border was larger for postsynaptic interneurons than CA1 pyramidal cells.
“However, Ali and Todorova (21) observed that the synchronicity ratio for CCK cells residing at the s.l.m.-s.r. border was larger for postsynaptic interneurons than CA1 pyramidal cells, suggesting that postsynaptic targets may influence synchronicity of release for certain CCK cell subtypes.”
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- Interpretationreasoning§ 3. NGFCs
This atypical form of neurotransmission arises from the unique axonal arborizations of NGFCs that emerge from the soma or dendrites to form a small dense plexus around the parent cell soma.
“This atypical form of neurotransmission arises from the unique axonal arborizations of NGFCs that emerges from the soma or dendrites to form a small dense plexus around the parent cell soma (FIGURES 3, 9I, and 13C).”
Quote in the paperSubstantial claim - Premisecitation§ 2. CCK-containing cells
Asynchronous release at a number of synapses has been attributed to the buildup of residual Ca2+ during periods of high activity.
“However, asynchronous release at a number of synapses has been attributed to the buildup of residual Ca2+ during periods of high activity (706, 868).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. CCK-containing cells
At CCK cell synapses, asynchronous release increases with elevation of extracellular Ca2+ concentration.
“At CCK cell synapses, asynchronous release increases with elevation of extracellular Ca2+ concentration (258).”
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- Premisecitation§ 2. CCK-containing cells
CCK cell action potential durations lengthen upon repetitive activation during trains.
“In addition, CCK cells fire action potentials with longer durations (>0.5 ms), which lengthen upon repetitive activation during trains further contrasting with their PV cell counterparts (182).”
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- Premisecitation§ 2. CCK-containing cells
CCK interneuron unitary IPSC amplitudes and latencies show large fluctuations due to weak coupling between their presynaptic N-type Ca2+ channels and release machinery.
“CCK interneuron unitary IPSC amplitudes and latencies show large fluctuations (258, 477), due to weak coupling between their presynaptic N-type Ca2+ channels and release machinery (64, 477) (FIGURE 13B).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 1. PV-containing interneurons
The synaptotagmin family member syt2 possesses rapid Ca2+ binding kinetics.
“The synaptotagmin family member syt2, which possesses rapid Ca2+ binding kinetics (1232), is highly enriched in PV cell axons (576).”
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- Premisecitation§ 2. CCK-containing cells
In paired recordings, asynchronous release at CCK synapses has a long temporal window of transmitter release that continues many 100s of milliseconds after termination of presynaptic firing.
“Indeed, in paired recordings, one striking feature of asynchronous release is the long temporal window of transmitter release that continues many 100s of milliseconds after termination of presynaptic firing (258, 477), underscoring that this form of inhibition is prolonged and temporally imprecise (FIGURE 13B).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 1. PV-containing interneurons
syt2 is highly enriched in PV cell axons.
“The synaptotagmin family member syt2, which possesses rapid Ca2+ binding kinetics (1232), is highly enriched in PV cell axons (576).”
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- Premisecitation§ 3. NGFCs
The presynaptic bouton density of NGFCs is among the highest of all hippocampal interneurons, with an average bouton density close to 42 per 100 μm of axon (interbouton separation 2.5 μm).
“Importantly, the presynaptic bouton density of NGFCs is among the highest of all hippocampal interneurons with an average bouton density close to 42 per 100 μm of axon (interbouton separation 2.5 μm) (102).”
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- Premisecitation§ 3. NGFCs
The bouton density of a single NGFC matches the release site density of five or six overlapping basket cell axons.
“Indeed, the bouton density of a single NGFC matches the release site density of five or six 6 overlapping basket cell axons (858).”
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- Interpretationcitation§ 2. CCK-containing cells
The difference in Ca2+ dependence between synchronous and asynchronous release observed at CCK synapses is consistent with the presence of two Ca2+ sensors at these presynaptic terminals.
“The difference in Ca2+ dependence between synchronous and asynchronous release observed at CCK synapses is consistent with the presence of two Ca2+ sensors at these presynaptic terminals (256, 258).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 1. PV-containing interneurons
Single axons of DG PVBCs differentially inhibit close versus distant principal cell targets.
“In a recent study, Bartos and colleagues (1058) observed that single axons of DG PVBCs differentially inhibited close versus distant principal cell targets.”
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- Premisecitation§ 2. CCK-containing cells
Transmission at CCK-containing cells and their downstream targets transitions from largely synchronous neurotransmitter release to asynchronous release during repetitive activation.
“An important feature of transmission at CCK-containing cells and their downstream targets is the transition from largely synchronous neurotransmitter release to asynchronous release during repetitive activation (21, 258, 477).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 1. PV-containing interneurons
PVBCs can display distance-dependent scaling.
“Despite the specializations designed to ensure high fidelity across the axonal arborization, PVBCs can display distance-dependent scaling.”
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- Interpretationreasoning§ 2. CCK-containing cells
CCK-containing cells show a distinct mode of neurotransmission that favors looser coupling and an asynchronous mode of transmitter release compared with PV-containing cells.
“CCK-containing cells show an altogether distinct mode of neurotransmission that favors looser coupling and an asynchronous mode of transmitter release compared with PV-containing cells (FIGURE 13B).”
Quote in the paperSubstantial claim - Premisecitation§ 3. NGFCs
The low pass coupling coefficient of connections is highly variable but is typically between 1 and 40% (with a mean coupling conductance of 1.6 nS).
“The low pass coupling coefficient of connections is highly variable but is typically between 1 and 40% (with a mean coupling conductance of 1.6 nS) (220, 488).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 3. NGFCs
Electrical synapses are rarely seen between principal cells.
“In contrast, electrical synapses are rarely seen between principal cells (901).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [901] Peters A, 1980, Adv Neurol
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- Premisecitation§ 3. NGFCs
Interneuron subtypes fire at specific phases of the oscillatory cycle.
“Moreover, the observations that specific interneuron subtypes are necessary for the generation of coherent cortical and hippocampal oscillations (333, 1200) and that interneuron subtypes fire at specific phases of the oscillatory cycle (586) suggest that synchronization among interneurons is critical for cortical circuit function (151).”
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- Premisenone given§ 3. NGFCs
Estimates of connectivity suggest that >50% of cells make within class electrical synapses.
“Estimates of connectivity suggest that >50% of cells make within class electrical synapses.”
Quote in the paperNot a substantial claim - Premisecitation§ 3. NGFCs
Specific interneuron subtypes are necessary for the generation of coherent cortical and hippocampal oscillations.
“Moreover, the observations that specific interneuron subtypes are necessary for the generation of coherent cortical and hippocampal oscillations (333, 1200) and that interneuron subtypes fire at specific phases of the oscillatory cycle (586) suggest that synchronization among interneurons is critical for cortical circuit function (151).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ 3. NGFCs
Synchronization among interneurons is critical for cortical circuit function.
“Moreover, the observations that specific interneuron subtypes are necessary for the generation of coherent cortical and hippocampal oscillations (333, 1200) and that interneuron subtypes fire at specific phases of the oscillatory cycle (586) suggest that synchronization among interneurons is critical for cortical circuit function (151).”
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- Premisecitation§ 3. NGFCs
Within hippocampus and neocortex, dendrodendritic or dendrosomatic electrical synapses are a common feature of many interneurons.
“Within hippocampus and neocortex, dendrodendritic or dendrosomatic electrical synapses are a common feature of many interneurons (80, 370, 371, 376, 398, 1084).”
Quote in the paperNot a substantial claim0 of 6 sources checked - Premisecitation§ 3. NGFCs
Sensory stimuli can trigger synchronous inhibitory activity across large populations of cortical cells.
“The observation that sensory stimuli could trigger synchronous inhibitory activity across large populations of cortical cells suggested that networks of certain interneuron subtypes were highly interconnected (220, 541, 1072).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ 3. NGFCs
During persistent firing, cells fire at frequencies ranging from 20 to 130 Hz, depending on the particular region.
“During persistent firing, cells fire at frequencies ranging from 20 to 130 Hz, depending on the particular region (1069).”
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- Premisenone given§ 3. NGFCs
Electrical synapses have unusual low pass filtering properties.
“Electrical synapses have unusual low pass filtering properties that provide essential clues to their function.”
Quote in the paperNot a substantial claim - Premisecitation§ 3. NGFCs
In PV-containing interneurons, steady-state persistent firing dominates at gamma frequencies close to 50 Hz.
“In PV-containing interneurons, steady-state persistent firing dominates at gamma frequencies close to 50 Hz (300).”
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- Premisecitation§ 3. NGFCs
Persistent firing is not blocked by GABAA, GABAB, AMPA, or NMDA receptor antagonists.
“Although the mechanism underlying the generation of persistent firing is at present unidentified, it is not blocked by GABAA, GABAB, AMPA, or NMDA receptor antagonists (1000).”
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- Premisecitation§ 3. NGFCs
A novel form of slow integration triggered in response to prolonged action potential activity is known as persistent or retroaxonal barrage firing.
“This novel form of slow integration is triggered in response to prolonged action potential activity and is known as persistent or retroaxonal barrage firing (300, 606, 1000, 1001, 1069, 300).”
Quote in the paperNot a substantial claim0 of 5 sources checked - Interpretationreasoning§ 3. NGFCs
In contrast to other interneuron subtypes that precisely target distinct subcellular domains, inhibition mediated by NGFCs generally lacks target cell and synaptic specificity.
“Second, in contrast to other interneuron subtypes that precisely target distinct subcellular domains, inhibition mediated by NGFCs generally lacks target cell and synaptic specificity.”
Quote in the paperSubstantial claim - Premisecitation§ 3. NGFCs
In somatosensory cortex, the separation between NGFC boutons and their dendrite targets averages 2.7 μm (range 1.1-5.0 μm).
“In somatosensory cortex, the separation between NGFC boutons and their dendrite targets averages 2.7 μm (range 1.1–5.0 μm) (858).”
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- Premisecitation§ 3. NGFCs
Many interneuron types are highly interconnected by connexin-36-containing electrical synapses or gap junctions.
“Although GABAergic interactions between interneurons have been implicated in the generation of synchronous activity (1190), the observation that many interneuron types were highly interconnected by connexin-36-containing electrical synapses (497, 1167) or gap junctions provided an important clue as to how large populations can be synchronized during oscillatory activity (220, 488).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisenone given§ 3. NGFCs
Electrical synapses between interneurons are made typically only between cells of the same class or subtype.
“Electrical synapses between interneurons are made typically only between cells of the same class or subtype.”
Quote in the paperNot a substantial claim - Interpretationcitation§ 3. NGFCs
Networks of certain interneuron subtypes are highly interconnected.
“The observation that sensory stimuli could trigger synchronous inhibitory activity across large populations of cortical cells suggested that networks of certain interneuron subtypes were highly interconnected (220, 541, 1072).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given§ 3. NGFCs
PVBCs are connected via both chemical and electrical synapses.
“PVBCs are connected via both chemical and electrical synapses.”
Quote in the paperNot a substantial claim - Premisecitation§ V. GLUTAMATE RECEPTORS
In situ hybridization and RT-PCR coupled with electrophysiological approaches revealed the presence of both inwardly rectifying, GluA2-lacking Ca2+-permeable (CP) AMPARs and GluA2-containing CI-AMPARs on inhibitory interneurons throughout the cortex and hippocampal formation.
“In situ hybridization and RT-PCR coupled with electrophysiological approaches subsequently revealed the presence of both inwardly rectifying, GluA2-lacking Ca2+-permeable (CP) AMPARs and GluA2-containing CI-AMPARs on inhibitory interneurons throughout the cortex and hippocampal formation (11, 51, 107, 388, 539, 769, 960).”
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- cites [388] source
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- cites [960] source
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- Premisecitation§ V. GLUTAMATE RECEPTORS
GluA4 expression increases over the first two postnatal weeks to generate receptors comprised of GluA1/GluA4 heteromers by adulthood.
“GluA4 expression increases over the first two postnatal weeks to generate receptors comprised of GluA1/GluA4 heteromers by adulthood (99, 388, 800, 886).”
Quote in the paperSubstantial claim0 of 4 sources checked - Premisecitation§ V. GLUTAMATE RECEPTORS
Early quantitative electron microscopy studies indicated that asymmetric synapses onto interneuron dendrites were enriched for GluA subunits, with little evidence for the "silent" synapses observed on principal cell dendrites that lacked AMPAR subunits and appear critical for synapse maturation.
“Early quantitative electron microscopy studies indicated that asymmetric synapses onto interneuron dendrites were enriched for GluA subunits, with little evidence for the “silent” synapses observed on principal cell dendrites that lacked AMPAR subunits and appear critical for synapse maturation (846).”
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- Premisenone given§ V. GLUTAMATE RECEPTORS
Most mature AMPAR on principal neurons are typically comprised of GluA1/2 or 2/3 heteromers, which are Ca2+-impermeable (CI) and possess nearly linear current-voltage relationships.
“Although most mature AMPAR on principal neurons are typically comprised of GluA1/2 or 2/3 heteromers, which are Ca2+-impermeable (CI) and possess nearly linear current-voltage relationships, early evidence indicated that many interneurons expressed AMPARs that differed markedly in these properties from their principal neuron counterparts (517, 874).”
Quote in the paperNot a substantial claim - Premisecitation§ 3. NGFCs
In CA1 PPA cells, persistent firing is attenuated by blocking voltage-gated Ca2+ channels.
“In CA1 PPA cells, persistent firing is attenuated by blocking voltage-gated Ca2+ channels (1001).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Early evidence indicated that many interneurons expressed AMPARs that differed markedly in these properties from their principal neuron counterparts.
“Although most mature AMPAR on principal neurons are typically comprised of GluA1/2 or 2/3 heteromers, which are Ca2+-impermeable (CI) and possess nearly linear current-voltage relationships, early evidence indicated that many interneurons expressed AMPARs that differed markedly in these properties from their principal neuron counterparts (517, 874).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation§ V. GLUTAMATE RECEPTORS
This receptor arrangement is critical for circuit recruitment of PV-containing interneurons to enforce temporal control over principal cells for efficient generation of large scale oscillatory activity.
“This receptor arrangement is critical for circuit recruitment of PV-containing interneurons to enforce temporal control over principal cells for efficient generation of large scale oscillatory activity (for review, see Refs. 67, 502).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 3. NGFCs
In PV-containing cells, persistent firing depends on Ih activation.
“In PV-containing cells, persistent firing depends on Ih activation (300).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Both CCK-containing and NOS/NPY-containing interneurons showed comparatively low but consistent levels of all four GluA transcripts compared with principal cell synapses.
“In contrast, both CCK-containing and NOS/NPY-containing interneurons showed comparatively low but consistent levels of all four GluA transcripts compared with principal cell synapses (1242).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Subsequent analysis of mRNA transcripts using fluorescent in situ hybridization revealed a high abundance of GluA1 and GluA3 in PV cells, equivalent to expression levels on principal cells.
“Subsequent analysis of mRNA transcripts using fluorescent in situ hybridization revealed a high abundance of GluA1 and GluA3 in PV cells, equivalent to expression levels on principal cells.”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Incorporation of GluA2 is key to the overall biophysical properties of the AMPAR.
“Of these subunits, incorporation of GluA2 is key to the overall biophysical properties of the receptor.”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Both CP- and CI-impermeable AMPARs had been observed in recordings from single CA3 stratum lucidum (s.l.) interneurons, which targeted each receptor subtype to postsynaptic sites innervated by distinct afferent projections.
“Moreover, both CP- and CI-impermeable AMPARs had been observed in recordings from single CA3 stratum lucidum (s.l.) interneurons, which targeted each receptor subtype to postsynaptic sites innervated by distinct afferent projections (1119).”
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- Interpretationnone given§ 3. NGFCs
Persistent firing likely provides a global "brake" on local excitability.
“Importantly, persistent firing, which likely provides a global “brake” on local excitability, occurs in NGFCs both in vitro and in vivo, although in vivo it occurs less frequently and requires more prolonged barrages of action potential activity for initiation in neocortical NGFCs (1069).”
Quote in the paperNot a substantial claim - Premisecitation§ V. GLUTAMATE RECEPTORS
GluA4 expression was significantly higher at PV synapses than non-PV synapses.
“However, GluA4 expression was significantly higher at PV synapses than non-PV synapses.”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Quantitative immunogold electron microscopy of the AMPAR subunits expressed at Schaffer collateral inputs onto CA1 s.r. interneurons revealed no differences in GluA1, GluA2, or GluA3 subunit expression between synapses onto PV-containing interneurons versus "non-PV" synapses.
“Quantitative immunogold electron microscopy of the AMPAR subunits expressed at Schaffer collateral inputs onto CA1 s.r. interneurons revealed no differences in GluA1, GluA2, or GluA3 subunit expression between synapses onto PV-containing interneurons versus “non-PV” synapses (1242).”
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- Interpretationcitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Integration of developing interneurons into the nascent circuit critically depends on NMDAR activity.
“Integration of developing interneurons into the nascent circuit critically depends on NMDAR activity.”
Quote in the paperSubstantial claim - Premisecitation§ V. GLUTAMATE RECEPTORS
In hippocampal principal cells, the vast majority of AMPARs interact with the TARP type 1 γ2 and γ8 isoforms, which alter surface expression, synaptic targeting kinetics, and plasticity.
“In hippocampal principal cells, the vast majority of AMPARs interact with the TARP type 1 γ2 and γ8 isoforms, which alter surface expression, synaptic targeting kinetics, and plasticity (524, 525).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
PV-containing interneurons possess the smallest NMDAR currents.
“However, given that PV-containing interneurons possess the smallest NMDAR currents (763), it is hard to reconcile the hypothesis that PV interneuron synaptic NMDAR hypofunction is an underpinning”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
In CA1 s.r. interneurons, exogenous kainate evokes inward currents in both GluK1 or GluK2 knockouts, suggesting functional receptor subunit redundancy.
“In CA1 s.r. interneurons, exogenous kainate evokes inward currents in both GluK1 or GluK2 knockouts, suggesting functional receptor subunit redundancy (816).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
In MGE-derived hippocampal interneurons of young mice, GluN2B-containing NMDARs play an important role in modulating excitation-spike coupling.
“In MGE-derived hippocampal interneurons of young mice, GluN2B-containing NMDARs play an important role in modulating excitation-spike coupling.”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
The developmental upregulation of GluA4 in PV-containing interneurons requires the coordinated expression of both NPTX2 and NPTXR.
“In a subsequent study, the developmental upregulation of GluA4 in PV-containing interneurons was observed to require the coordinated expression of both NPTX2 and NPTXR (886).”
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- Interpretationreasoning§ V. GLUTAMATE RECEPTORS
These data suggest a prominent role for the γ2 in AMPAR expression at excitatory synapses onto PV-containing neurons.
“These data suggest a prominent role for the γ2 in AMPAR expression at excitatory synapses onto PV-containing neurons.”
Quote in the paperSubstantial claim - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
The density of PV-positive interneurons in somatosensory cortex of transgenic mice with selective deletion of GluN2B from GAD67-positive interneurons is comparable to wild-type mice.
“However, the density of PV-positive interneurons in somatosensory cortex of transgenic mice with selective deletion of GluN2B from GAD67-positive interneurons was comparable to wild-type mice (574).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
AMPAR number was unchanged at synapses onto both PV- and non-PV cell groups in both γ3 and γ8 knockouts.
“In contrast, AMPAR number was unchanged at synapses onto both PV- and non-PV cell groups in both γ3 and γ8 knockouts (1242).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1242] source
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
KR-mediated currents through homomeric or heteromeric GluK1 or GluK2-containing KRs have been observed in numerous interneuron subtypes.
“KR-mediated currents through either homomeric or heteromeric GluK1 or GluK2-containing KRs have been observed in numerous interneuron subtypes (230, 332, 348, 867, 883, 920).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
The slower kinetics of GluN2B-containing NMDARs influence synaptic integration properties to regulate both the summation and timing of action-potential generation.
“The slower kinetics of GluN2B-containing NMDARs influence the synaptic integration properties to regulate both the summation and timing of action-potential generation (763).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Loss of NMDARs in PV-containing interneurons at early postnatal ages triggers behavioral deficits associated with schizophrenia.
“Loss of NMDARs in PV-containing interneurons at early postnatal ages triggers behavioral deficits associated with schizophrenia including psychomotor agitation, anhedonia, reduced pre-pulse inhibition of acoustic startle, deficits in nesting/mating, and social withdrawal (82), supporting an NMDAR hypofunction theory of schizophrenia (for reviews, see Refs. 234, 235).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
At synapses with low NMDA/AMPAR ratios, EPSPs trigger only single action potential firing with no substantial after depolarizing phase.
“In contrast, in synapses with low NMDA/AMPAR ratios, EPSPs trigger only single action potential firing with no substantial after depolarizing phase (661).”
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- Interpretationcitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
This regulation by NPTX2 critically dictates PV-containing interneuron recruitment to maintain E/I balance in the face of perturbations in network activity.
“This regulation by NPTX2 critically dictates PV-containing interneuron recruitment to maintain E/I balance in the face of perturbations in network activity (189).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Interneurons predominantly express GluK1 and GluK2 (with lower levels of GluK3) at either pre- and postsynaptic sites.
“Although all subunits are widely expressed throughout the central nervous system, interneurons predominantly express GluK1 and GluK2 (with lower levels of GluK3) at either pre- and postynaptic sites (143, 332; for review, see Refs. 11, 171).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Genetic deletion of GluN2B in hippocampal interneurons leads to a reduction in the frequency of AMPAR-mediated mEPSCs observed onto CA1 s.o. interneurons.
“Genetic deletion of GluN2B in hippocampal interneurons leads to a reduction in the frequency of AMPAR-mediated mEPSCs observed onto CA1 s.o. interneurons (574).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [574] source
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Elimination of GluN1 and GluN2B, but not GluN2A, in cortical CGE derived interneurons produces cell type specific (reelin-positive, but not VIP-containing cells) stunting of dendritic and axonal morphology.
“Elimination of GluN1 and GluN2B, but not GluN2A, in cortical CGE derived interneurons produces cell type specific (reelin-positive, but not VIP-containing cells) stunting of dendritic and axonal morphology (261).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
Only low expression of γ8 TARP was observed across all interneuron subtypes tested.
“In contrast, only low expression of γ8 TARP was observed across all interneuron subtypes tested (1242).”
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- Premisecitation§ V. GLUTAMATE RECEPTORS
TARPs γ2 and γ3 are enriched in PV-containing interneurons compared with CCK- and nNOS/NPY-containing interneurons.
“A recent study combining FISH and immunohistochemistry and quantitative electron microscopy illustrated that TARPs γ2 and γ3 are enriched in PV-containing interneurons compared with CCK- and nNOS/NPY-containing interneurons.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1242] source
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Functional mapping of KRs using uncaging revealed a continuous density of KRs across dendrites of CA1 s.o. O-LM and trilaminar interneurons.
“Functional mapping of KRs using uncaging methods revealed a continuous density of KRs across the dendrites of CA1 s.o. O-LM and “trilaminar” (sic) interneurons (1245).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Neto1/Neto2 are auxiliary KR subunits capable of regulating almost every parameter of receptor function.
“Neuropilin- and tolloid-like proteins (Neto1/Neto2) are auxiliary KR subunits capable of regulating almost every parameter of receptor function.”
Quote in the paperNot a substantial claim - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Evoked GluK1-containing KR synaptic events make only a modest contribution (~10% of the total current) when synaptic transmission is driven by repetitive activity.
“Indeed, evoked GluK1-containing KR synaptic events make only a modest contribution (~10% of the total current) when synaptic transmission is driven by repetitive activity (867).”
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- Premisecitation§ 2. Group II and III mGluRs
Electron microscopic immunocytochemistry has revealed expression of group III family members mGluR4, mGluR7a, mGluR7b, and mGluR8a in the presynaptic active zone of GABAergic terminals onto hippocampal CA1 and CA3 interneurons (but not onto pyramidal cells).
“Electron microscopic immunocytochemistry has revealed the expression of group III family members, mGluR4, mGluR7a, mGluR7b, and mGluR8a in the presynaptic active zone of GABAergic terminals onto hippocampal CA1 and CA3 interneurons (but not onto pyramidal cells) (592, 1004).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ 2. Group II and III mGluRs
GABA release from interneuron axons is modulated by presynaptic mGluRs.
“GABA release from interneuron axons is modulated by presynaptic mGluRs.”
Quote in the paperSubstantial claim - Premisecitation§ 2. Group II and III mGluRs
Imaging of interneuron axonal boutons demonstrated that neighboring varicosities often show heterogeneous sensitivity to group III mGluR activation, consistent with target cell dependence of mGluR expression.
“Imaging of interneuron axonal boutons demonstrated that neighboring varicosities often showed heterogeneous sensitivity to group III mGluR activation, consistent with the target cell dependence of mGluR expression (969, 1004, 1005).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
In hippocampus, exogenous kainate reduces the amplitude and Pr of evoked IPSCs onto CA1 pyramidal cells.
“In hippocampus, exogenous kainate reduces the amplitude and Pr of evoked IPSCs onto CA1 pyramidal cells (208, 231, 734, 951) (however cf. with Refs. 231, 332).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
High-frequency stimulation of CA1 Schaffer collateral afferents transiently depresses inhibitory transmission onto pyramidal cells via a mechanism involving glutamate spillover activating presynaptic GluK1-containing receptors on CB1R-positive interneuron presynaptic terminals.
“High-frequency stimulation of CA1 Schaffer collateral afferents transiently depresses inhibitory transmission onto pyramidal cells via a mechanism involving glutamate spillover activating presynaptic GluK1-containing receptors on CB1R-positive interneuron presynaptic terminals (701).”
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- Premisecitation§ 1. Group I mGluRs
Application of the nonselective mGluR ligand trans-ACPD to CA1 s.o. SST-containing O-LM interneurons and CB-positive interneurons triggers slow oscillatory inward currents.
“Application of the nonselective mGluR ligand trans-ACPD to CA1 s.o. SST-containing O-LM interneurons (768) and CB-positive interneurons (1156) triggered slow oscillatory inward currents (768, 1156, 1217).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
At dentate gyrus mossy fiber axons to CA3 pyramidal cell synapses, Neto1 regulates binding affinity, kinetics, and synaptic targeting of native GluK2-containing postsynaptic KRs.
“At dentate gyrus mossy fiber axons to CA3 pyramidal cell synapses, Neto1 regulates binding affinity, kinetics, and synaptic targeting of native GluK2-containing postsynaptic KRs (1056, 1094, 1224).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisenone given§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
KRs are expressed on axonal presynaptic terminals of certain interneuron types, where they regulate neurotransmitter release.
“KRs are also expressed on axonal presynaptic terminals of certain interneuron types, where they serve to regulate neurotransmitter release.”
Quote in the paperNot a substantial claim - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
GluK1 antagonists reduce the frequency of hippocampal theta oscillations in vivo.
“Indeed, GluK1 antagonists reduce the frequency of hippocampal theta oscillations in vivo (515).”
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- Premisecitation§ I. Delta Glutamate Receptors
RT-PCR from interneurons of the s.r. and s.l.m. revealed highest expression of GluD1 (>90% of GluD transcripts) with much lower expression of GluD2.
“RT-PCR from interneurons of the s.r. and s.l.m. revealed highest expression of GluD1 (representing >90% of GluD transcripts) with a much lower expression of GluD2.”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
This spillover mechanism requires the concerted activation of the eCB system, presynaptic CB1Rs and GluK1-containing KRs.
“This spillover mechanism requires the concerted activation of the eCB system, presynaptic CB1Rs and GluK1-containing KRs (701).”
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Activation of presynaptic KRs preferentially reduces synchronous, but spares asynchronous transmitter release.
“Activation of presynaptic KRs preferentially reduces synchronous, but spares asynchronous transmitter release (256).”
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- Premisecitation§ 2. Group II and III mGluRs
Modulation of inhibitory transmission by group III mGluRs occurs via a reduction of Ca2+ influx through N-type channels but not P/Q channels.
“Modulation of inhibitory transmission by group III mGluRs occurs via a reduction of Ca2+ influx through N-type channels but not P/Q channels (969).”
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- Premisecitation§ 2. Group II and III mGluRs
Activation of presynaptic mGluRs reduces transmitter release by altering Ca2+ entry into the presynaptic terminals.
“Activation of presynaptic mGluRs reduces transmitter release by altering Ca2+ entry into the presynaptic terminals (283, 514).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Neto1 and Neto2 colocalize with GluK subunits (1/2/5) in SST-, CCK-, and PV-containing interneurons.
“Neto1 and Neto2 colocalize with GluK subunits (1/2/5) in SST-, CCK-, and PV-containing interneurons (Wyeth, Pelkey, and McBain, unpublished observation).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wyeth, Pelkey, and McBain, unpublished observation
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- Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal Pentraxins
Cossart and colleagues observed spontaneous KR-mediated synaptic events with slow kinetics (decay tau's ~10 ms) onto CA1 s.o. interneurons, primarily O-LM cells, that occurred in the absence of a detectable AMPAR component.
“However, Cossart and colleagues (229, 420) observed spontaneous KR-mediated synaptic events with slow kinetics (decay tau’s ~10 ms) onto CA1 s.o. interneurons, primarily O-LM cells, that occurred in the absence of a detectable AMPAR component.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
This form of LTP requires cooperative interaction between group I mGluRs or M1 mAChRs by an as yet unknown mechanism.
“This form of LTP requires cooperative interaction between group I mGluRs or M1 mAChRs by an as yet unknown mechanism (648).”
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- Premisecitation§ 2. Group II and III mGluRs
Transmission between CA3 s.r. interneurons and pyramidal cells is reduced by the group II agonist DCG-IV.
“Poncer et al. (916) demonstrated that transmission between CA3 s.r. interneurons and pyramidal cells was reduced by the group II agonist DCG-IV.”
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- Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
Frequency-dependent facilitation between pyramidal cells and bitufted cells is more sensitive to presynaptic Ca2+ buffering than is depression onto multipolar cells.
“An elegant study by Koester and Sakmann (591) demonstrated that frequency-dependent facilitation between pyramidal cells and bitufted cells is more sensitive to presynaptic Ca2+ buffering than is depression onto multipolar cells.”
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- Interpretationreasoning§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
The postsynaptic locus for induction and presynaptic locus for expression of this NMDAR-independent form of LTP implies retrograde signaling between the post- and presynaptic sites.
“The postsynaptic locus for induction and presynaptic locus for expression of this NMDAR-independent form of LTP implies retrograde signaling between the post- and presynaptic sites.”
Quote in the paperSubstantial claim - Premisecitation§ 2. Group II and III mGluRs
mGluR8-positive boutons, which also expressed VIP or mGluR7, are selectively targeted to muscarinic receptor M2-containing interneurons.
“mGluR8-positive boutons, which also expressed VIP or mGluR7, are selectively targeted to muscarinic receptor M2-containing interneurons.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [326] source
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- Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
Markram et al. using triple patch-clamp recordings were first to demonstrate that a presynaptic train of action potentials in a cortical layer 5 pyramidal cell simultaneously triggered short-term facilitation of transmission onto an interneuron target and depressing synaptic events onto a pyramidal cell target.
“Markram et al. (749) using triple patch-clamp recordings were first to demonstrate that a presynaptic train of action potentials in a cortical layer 5 pyramidal cell simultaneously triggered short-term facilitation of transmission onto an interneuron target and depressing synaptic events onto a pyramidal cell target (FIGURE 16A).”
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- Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
A single axon possesses different release properties at adjacent boutons onto differing postsynaptic targets.
“There is now overwhelming evidence that a single axon possesses different release properties at adjacent boutons onto differing postsynaptic targets (888).”
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- Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
Elfn1 is expressed at pyramidal cell synapses onto SST-containing cells but not PV-containing interneurons in both the CA1 and dentate gyrus.
“Elfn1 is expressed at pyramidal cell synapses onto SST-containing cells but not PV-containing interneurons in both the CA1 and dentate gyrus (1073, 1106).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisereasoning§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
The major "types" of interneuron plasticity center on activation of mGluRs and CP-AMPARs.
“Instead, the major “types” of interneuron plasticity center on activation of mGluRs and CP-AMPARs. Interested readers are directed to several excellent reviews that discuss the history and the nuances of this research (619, 620, 625, 802).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
A 10-fold variation in single action potential evoked Ca2+ transients was observed across different boutons of a single layer 2/3 pyramidal neuron despite all boutons using P/Q-type Ca2+ channels.
“Indeed, a 10-fold variation in single action potential evoked Ca2+ transients was observed across different boutons of a single layer 2/3 pyramidal neuron despite all boutons using P/Q-type Ca2+ channels (591) (FIGURE 16C).”
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- Premisereasoning§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
An entirely postsynaptic form of short-term plasticity exists at glutamatergic synapses made onto CP-AMPARs.
“An entirely postsynaptic form of short-term plasticity exists at glutamatergic synapses made onto CP-AMPARs.”
Quote in the paperSubstantial claim - Premisenone given§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
Short-term depression enforces a narrow temporal window for successive synaptic events to summate and trigger action potential activity, thereby progressively weakening any influence of the presynaptic cell during repetitive activation.
“In contrast, short-term depression acts to enforce a narrow temporal window for successive synaptic events to summate and to trigger action potential activity, thereby progressively weakening any influence that the presynaptic cell may have during repetitive activation.”
Quote in the paperNot a substantial claim - Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
CP-AMPARs act as coincidence detectors between an excitatory afferent input and synapses that are hyperpolarized or inactive.
“The “anti-Hebbian” tag is derived from the observation that CP-AMPARs act as coincidence detectors between an excitatory afferent input and synapses that are hyperpolarized or inactive (617, 618, 625).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
A train of action potentials in a cortical layer 2/3 pyramidal cell presynaptic to two different inhibitory interneuron targets triggered short-term facilitation onto a bitufted interneuron and depression of transmission onto a multipolar interneuron.
“A train of action potentials in the presynaptic pyramidal cell triggered short-term facilitation onto a bitufted interneuron and depression of transmission onto a multipolar interneuron (940).”
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- Premisecitation§ C. CA1 Hippocampal Interneuron LTD
A high-frequency stimulation paradigm that typically triggers LTP at synapses onto principal cells induced LTD at synapses onto s.r. interneurons.
“One of the first reports of long-lasting plasticity at excitatory synapses onto hippocampal interneurons came from observations that a high-frequency stimulation paradigm that typically triggers LTP at synapses onto principal cells induced LTD at synapses onto s.r. interneurons (774).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [774] source
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- Premisecitation§ 1. CA3 pyramidal–s.r. interneuron synapses
With NMDARs unblocked, the same induction paradigm triggers an NMDAR-dependent form of LTP or LTD that is entirely dependent on the postsynaptic membrane potential.
“Intriguingly, with NMDARs unblocked, the same induction paradigm triggers an NMDAR-dependent form of LTP or LTD that is entirely dependent on the postsynaptic membrane potential (626).”
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- Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapses
At CP-AMPAR synapses, the same induction protocol triggers presynaptic NMDAR-independent LTD.
“At CP-AMPAR synapses, the same induction protocol triggers presynaptic NMDAR-independent LTD (662).”
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- Premisecitation§ 1. CA3 pyramidal–s.r. interneuron synapses
High-frequency stimulation of CA3 afferents onto unidentified s.r. interneurons triggers an NMDAR-independent form of LTD at CP-AMPAR synapses that arises only when the postsynaptic membrane potential is hyperpolarized in a manner akin to that described as "anti-Hebbian" in CA1.
“High-frequency stimulation of CA3 afferents onto unidentified s.r. interneurons triggers an NMDAR-independent form of LTD at CP-AMPAR synapses that arises only when the postsynaptic membrane potential is hyperpolarized in a manner akin to that described as “anti-Hebbian” in CA1 (627).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [627] source
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- Premisecitation§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapses
In CA3 s.r. and s.l.m. interneurons that receive both CA3 pyramidal cell recurrent collateral and mossy fiber inputs, there appears to be a compartmentalization of synaptic plasticity.
“In CA3 s.r. and s.l.m. interneurons that receive both CA3 pyramidal cell recurrent collateral and mossy fiber inputs, there appears to be a compartmentalization of synaptic plasticity (379).”
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- Premisecitation§ C. CA1 Hippocampal Interneuron LTD
Like LTP at synapses onto interneurons, this LTD required group I mGluRs.
“Like LTP at synapses onto interneurons, this LTD required group I mGluRs.”
Quote in the paperSubstantial claim - Premisenone given§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapses
At mossy fiber synapses onto CA3 s.l.m interneurons, high-frequency stimulation induces a bidirectional form of NMDAR-independent plasticity.
“At mossy fiber synapses onto CA3 s.l.m interneurons, high-frequency stimulation induces a bidirectional form of NMDAR-independent plasticity.”
Quote in the paperNot a substantial claim - Premisenone given§ 4. Mossy fiber-dentate gyrus basket cell synapses
Perforant pathway synapses made onto CI-AMPARs do not show associative LTP.
“In contrast, perforant pathway synapses made onto CI-AMPARs do not show associative LTP.”
Quote in the paperSubstantial claim - Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapses
Mossy fiber inputs onto CP-AMPAR containing synapses on DG PVBCs express an NMDAR-independent form of LTP in response to high-frequency stimulation.
“To complicate matters even further, mossy fiber inputs onto CP-AMPAR containing synapses on DG PVBCs express an NMDAR-independent form of LTP in response to high-frequency stimulation (23).”
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- Interpretationreasoning§ 4. Mossy fiber-dentate gyrus basket cell synapses
These two forms of LTP appear to largely correlate with cellular origins in either the MGE or CGE.
“Of interest, these two forms of LTP appear to largely correlate with cellular origins in either the MGE or CGE.”
Quote in the paperNot a substantial claim - Premisecitation§ C. CA1 Hippocampal Interneuron LTD
This LTD was heterosynaptic, i.e., unstimulated synapses onto the same interneuron were also depressed.
“This LTD was heterosynaptic, i.e., unstimulated synapses onto the same interneuron were also depressed (774).”
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- Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
Use of nitric oxide, cannabinoid, and TRPV1 receptor antagonists has failed to implicate any of the more "conventional" retrograde messenger systems.
“At this time it is unclear what this signaling mechanism may be, but the use of nitric oxide, cannabinoid, and TRPV1 receptor antagonists has failed to implicate any of the more “conventional” retrograde messenger systems (834).”
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- Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapses
Small filopodial extensions from larger mossy fiber boutons form en passant or terminal synapses onto inhibitory interneurons within the hilar or CA3 subfields.
“In contrast, small filopodial extensions emanate from these larger mossy fiber boutons to form either en passant or terminal synapses onto inhibitory interneurons within the hilar or CA3 subfields.”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapses
Synapses onto many interneuron types lack any clear form of plasticity and simply follow the passive propagation of plasticity induced at excitatory synapses onto principal cells, which acts to increase their afferent output into the hippocampal network.
“Indeed, progress has been extremely slow in defining clear rules for interneuron plasticity, since synapses onto many interneuron types lack any clear form of plasticity and simply follow the “passive propagation” of plasticity induced at excitatory synapses onto principal cells, which acts to increase their afferent output into the hippocampal network (619, 720, 771).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ 2. Mossy fiber-stratum lucidum interneuron synapses
The presence or absence of mGluR7b at these synapses acts as a bidirectional switch that dictates the direction of plasticity by governing whether a PKC- or cAMP-mediated LTD or LTP is triggered.
“Thus the presence or absence of mGluR7b at these synapses acts as a bidirectional switch that dictates the direction of plasticity at these synapses by governing whether a PKC- or cAMP-mediated LTD or LTP is triggered, respectively.”
Quote in the paperSubstantial claim - Premisenone given§ 4. Mossy fiber-dentate gyrus basket cell synapses
Cells derived from the CGE typically possess large synaptic NMDAR conductances through GluN2B-containing NMDARs.
“Cells derived from the CGE typically possess large synaptic NMDAR conductances through GluN2B-containing NMDARs.”
Quote in the paperSubstantial claim - Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONS
CA1 s.o. interneurons in the αCaMKII T286A mutant possess normal NMDAR-dependent LTP unlike principal cells.
“Indeed, CA1 s.o. interneurons in the αCaMKII T286A mutant possess normal NMDAR-dependent LTP unlike principal cells (632).”
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- Interpretationreasoning§ 4. Mossy fiber-dentate gyrus basket cell synapses
Given the known synaptic properties of these cells, it seems extremely likely that developmental origin will determine which type of LTP an interneuron expresses.
“This differential expression of LTP between MGE- versus CGE-derived interneurons has not been rigorously determined, but given the known synaptic properties of these cells, it seems extremely likely that developmental origin will determine which type of LTP an interneuron expresses.”
Quote in the paperNot a substantial claim - Premisecitation§ 4. Interneuron targets of NGFCs
These remarkably slow kinetics are not fully attributable to dendritic filtering, asynchronous release, spillover, nor the properties of the GABAARs themselves but are primarily due to the spatiotemporal profile of GABA release from this interneuron subtype.
“These remarkably slow kinetics are not fully attributable to dendritic filtering, asynchronous release, spillover, nor the properties of the GABAARs themselves (however, see Refs. 483, 1264) but are primarily due to the spatiotemporal profile of GABA release from this interneuron subtype (see sect. IVL) (167, 550, 870, 1074).”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationreasoning§ 1. Interneuron targets of PV-expressing cells
Within the various PV-expressing populations of interneurons, specific connectivity rules exist.
“Thus, within the various PV-expressing populations of interneurons, specific connectivity rules exist.”
Quote in the paperNot a substantial claim - Premisecitation§ 3. Interneuron targets of SST-expressing cells
Paired electrophysiological recordings of presynaptic identified O-LM interneurons reveal action potential-dependent GABAAR-mediated responses on various interneuron subtypes including CCKBCs, SCAs, PPAs, and NGFCs.
“Paired electrophysiological recordings of presynaptic identified O-LM interneurons reveal action potential-dependent GABAAR-mediated responses on various interneuron subtypes including CCKBCs, SCAs, PPAs, and NGFCs (299).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [299] source
Not checked in the free run.
- Premisecitation§ 4. Interneuron targets of NGFCs
Inhibition between NGFCs results in GABAAR-mediated IPSCs with decay times an order of magnitude larger that have been termed GABAA,slow.
“However, in contrast to the fast synaptic inhibitory responses that occur on PV cells, inhibition between NGFCs results in GABAAR-mediated IPSCs with decay times an order of magnitude larger that have been termed GABAA,slow (48, 167, 870, 1086).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ 4. Interneuron targets of NGFCs
Electrophysiological recordings from pairs of NGFCs demonstrate a marked functional connectivity with each other.
“Electrophysiological recordings from pairs of NGFCs demonstrate a marked functional connectivity with each other (48, 550, 926, 1074).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ 1. Interneuron targets of PV-expressing cells
PV-expressing interneurons in CA1 and DG innervate each other as evidenced by synaptic boutons originating from this subtype at symmetric synapses along the somatodendritic axis of postsynaptic PV labeled interneurons.
“PV-expressing interneurons in CA1 and DG innervate each other as evidenced by the identification of synaptic boutons originating from this subtype at symmetric synapses, indicative of an inhibitory phenotype, along the somatodendritic axis of postsynaptic PV labeled interneurons (8, 440).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 2. Interneuron targets of CCK-expressing cells
CCK interneurons produce marked asynchronous GABAAR-mediated responses onto connected principal cells due to a relatively weak coupling between N-type calcium channels and the GABA release machinery in their presynaptic terminals.
“In contrast to the temporally precise PV interneuron inhibition, CCK interneurons produce marked asynchronous GABAAR-mediated responses onto connected principal cells due to a relatively weak coupling between N-type calcium channels and the GABA release machinery in their presynaptic terminals (21, 64, 477).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 3. Interneuron targets of SST-expressing cells
In dentate gyrus, SST-expressing HIPP interneurons impart GABAAR inhibition onto each another, albeit with a lower connectivity rate when compared with other homotypic interactions between CCK HICAP-CCK HICAP and PVBC-PVBC pairs that occur in this region.
“However, in dentate gyrus, the O-LM equivalent, SST-expressing HIPP interneurons impart GABAAR inhibition onto each another, albeit with a lower connectivity rate when compared with other homotypic interactions between CCK HICAP-CCK HICAP and PVBC-PVBC pairs that occur in this region (980).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [980] source
Not checked in the free run.
- Premisecitation§ VII. GABA RECEPTORS
Interneurons also impinge on each other providing inhibitory control of inhibition itself.
“However, it is evident that interneurons also impinge on each other providing inhibitory control of inhibition itself (186).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [186] source
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- Premisecitation§ 2. Interneuron targets of CCK-expressing cells
This mode of release is also evident at CCK-CCK synapses including those between CCKBCs resulting in a more temporally variable, prolonged inhibition compared with that seen at PV-PV synapses.
“Interestingly, this mode of release is also evident at CCK-CCK synapses including those between CCKBCs resulting in a more temporally variable, prolonged inhibition compared with that seen at PV-PV synapses (258).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [258] source
Not checked in the free run.
- Premisenone given§ 5. Interneuron specific cells
THIP possesses an extremely high efficacy for δ-containing GABAARs that is much greater than that of GABA itself.
“Additionally, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) possesses an extremely high efficacy for δ-containing GABAARs that is much greater than that of GABA itself.”
Quote in the paperNot a substantial claim - Premisenone given§ 5. Interneuron specific cells
ISI cells display a remarkable selectivity of their postsynaptic partners primarily targeting other interneurons whilst typically avoiding principal cells.
“As the name suggests, ISI cells display a remarkable selectivity of their postsynaptic partners primarily targeting other interneurons whilst typically avoiding principal cells.”
Quote in the paperSubstantial claim - Premisecitation§ 5. Interneuron specific cells
Increasing tonic inhibition in hilar SST cells via ectopic expression of α6 and δ subunits reduces experimentally induced bursting of IPSCs impinging on granule cells.
“Conversely, increasing tonic inhibition in hilar SST cells via ectopic expression of α6 and δ subunits reduces experimentally induced bursting of IPSCs impinging on granule cells (1109).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1109] source
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- Premisecitation§ 5. Interneuron specific cells
The δ subunit is particularly abundant in PV interneurons and NGFCs with little or no detectable levels observed in SST-, CB-, or CR-expressing subtypes.
“The δ subunit is particularly abundant in PV interneurons (320, 788, 1256) and NGFCs (316, 858) with little or no detectable levels observed in SST-, CB-, or CR-expressing subtypes (788).”
Quote in the paperNot a substantial claim0 of 5 sources checked - Premisenone given§ 5. Interneuron specific cells
The α5 and δ subunits containing extrasynaptic GABAARs possess a much higher affinity and minimal desensitization to GABA than synaptic receptors.
“The α5 and δ subunits containing extrasynaptic GABAARs possess a much higher affinity and minimal desensitization to GABA than synaptic receptors.”
Quote in the paperNot a substantial claim - Premisenone given§ 5. Interneuron specific cells
The neurosteroids allopregnanolone and tetrahydrodeoxycorticosterone are the most potent endogenous modulators of GABAARs.
“The most potent endogenous modulators of GABAARs are the neurosteroids allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC).”
Quote in the paperNot a substantial claim - Premisecitation§ 5. Interneuron specific cells
A population of GABAergic medial septal neurons specifically innervate hippocampal interneurons via long-range projections providing regulation of theta frequency synchronization.
“In addition to entorhinal cortical long-range inhibitory projections described earlier, a population of GABAergic medial septal neurons specifically innervate hippocampal interneurons via long-range projections providing regulation of theta frequency synchronization (351, 438, 1118).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 5. Interneuron specific cells
Expression of the δ subunit itself can be altered in part due to changes in the levels of circulating neurosteroids that occur during stress, puberty, menstrual cycle, and pregnancy.
“Interestingly, expression of the δ subunit itself can be altered in part due to changes in the levels of circulating neurosteroids that occur during stress, puberty, menstrual cycle, and pregnancy (726, 732, 733, 807).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ 5. Interneuron specific cells
GABAARs containing α1-3 and γ subunits versus those comprised of α4-6 and δ subunits are predominantly located at synaptic and extrasynaptic locations, respectively.
“The subunit composition dictates the trafficking of the receptor complex, and generally speaking, GABAARs containing α1–3 and γ subunits versus those comprised of α4–6 and δ subunits are predominantly located at synaptic and extrasynaptic locations, respectively (81, 317, 410).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ 5. Interneuron specific cells
Tonic inhibition has been described in interneurons with soma located in the m.l. of DG and CA1 s.r.
“This distinct inhibition mode has been described in interneurons with soma located in the m.l. of DG and CA1 s.r. (409, 659, 1038, 1256).”
Quote in the paperNot a substantial claim0 of 4 sources checked - Premisecitation§ 5. Interneuron specific cells
Plasticity of δ subunits on PV-expressing interneurons is linked to alterations of γ oscillatory activity that may explain memory and cognitive dysfunctions known to occur during estrus and pregnancy.
“In particular, plasticity of δ subunits on PV-expressing interneurons is linked to alterations of γ oscillatory activity that may explain memory and cognitive dysfunctions known to occur during estrus and pregnancy (320, 321).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ 5. Interneuron specific cells
Ablation of the δ subunit reduces THIP-mediated currents in interneuron populations, including PV subtypes.
“As expected, ablation of the δ subunit reduces THIP-mediated currents in interneuron populations, including PV subtypes (739).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [739] source
Not checked in the free run.
- Premisenone given§ 5. Interneuron specific cells
ISI-3 interneurons express VIP and CR.
“ISI-3 interneurons express VIP and CR, and recently, the postsynaptic partners of ISI-3 interneurons have been identified at a functional level.”
Quote in the paperNot a substantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Excitatory afferent inputs onto interneurons are stronger than equivalent inputs onto principal cells.
“In general, excitatory afferent inputs onto interneurons are stronger than the equivalent inputs onto principal cells (522).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [522] source
Not checked in the free run.
- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
The postsynaptic cell could still achieve the same maximal firing rate, albeit in response to a greater excitatory conductance input.
“In other words, the postsynaptic cell could still achieve the same maximal firing rate, albeit in response to a greater excitatory conductance input.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Particularly high levels of GABABRs are found on somatodendritic regions of CCK cells.
“Particularly high levels of GABABRs are found on somatodendritic regions of CCK cells (115, 1024).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Local circuit interneuron axons possess considerable diversity in the targeting of their downstream postsynaptic domains.
“As described in section II, local circuit interneuron axons possess considerable diversity in the targeting of their downstream postsynaptic domains (352, 582, 1036) (FIGURE 1).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
The relative size of GABABR-mediated currents among the various CCK subtypes significantly differ with larger responses noted in CCKBCs compared with those observed in SCAs or PPAs.
“However, the relative size of GABABR-mediated currents among the various CCK subtypes significantly differ with larger responses noted in CCKBCs compared with those observed in SCAs or PPAs (FIGURE 18) (115).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [115] source
Not checked in the free run.
- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
NGFCs mediate postsynaptic GABABR-mediated responses on other NGFCs and principal cells even after a single action potential.
“It is evident that NGFCs mediate postsynaptic GABABR-mediated responses on other NGFCs and principal cells even after a single action potential (48, 927, 1086).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Volume transmission by NGFCs also results in presynaptic GABABR activation on axon terminals of both PCs and other interneurons in a paracrine manner to modulate neurotransmitter release in cortical circuits.
“Volume transmission by NGFCs also results in presynaptic GABABR activation on axon terminals of both PCs and other interneurons in a paracrine manner to modulate neurotransmitter release in cortical circuits (204, 858).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Dentate gyrus NGFCs impart GABAA,slow responses on molecular layer interneurons.
“As mentioned, dentate gyrus NGFCs impart GABAA,slow responses on molecular layer interneurons (48), but whether these same interactions result in additional postsynaptic GABABR responses was not tested.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] source
Not checked in the free run.
- Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Postsynaptic GABABR-mediated signaling preferentially occurs in perisomatic versus dendritic targeting CCK subtypes.
“Thus, as with PV cells, postsynaptic GABABR-mediated signaling preferentially occurs in perisomatic versus dendritic targeting CCK subtypes (FIGURE 18).”
Quote in the paperNot a substantial claim - Premisenone given§ C. GABAB Receptor-Mediated Inhibition
SST-containing hippocampal O-LM cells or cortical Martinotti cells send their largely unbranching axons across several subfields to target the most distal dendritic portions of pyramidal cells.
“In contrast, SST-containing hippocampal O-LM cells or cortical Martinotti cells send their largely unbranching axons across several subfields to target the most distal dendritic portions of pyramidal cells (FIGURE 3).”
Quote in the paperNot a substantial claim - Premisereasoning§ C. GABAB Receptor-Mediated Inhibition
Transmission onto perisomatic versus dendritic targets provides fundamentally different forms of inhibitory synaptic control.
“Transmission onto perisomatic versus dendritic targets provides fundamentally different forms of inhibitory synaptic control.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
In most circuits, the short latency of feedforward inhibition enforces a narrow temporal window for action potential firing in principal cells.
“In most circuits the short latency of feedforward inhibition enforces a narrow temporal window for action potential firing in principal cells (922).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [922] source
Not checked in the free run.
- Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Any input that activates monosynaptic excitatory input onto principal cells will almost always trigger disynaptic inhibitory input to generate feedforward inhibition of the principal cells.
“This arrangement ensures that any input that activates monosynaptic excitatory input onto principal cells will almost always trigger disynaptic inhibitory input to generate feedforward inhibition of the principal cells (FIGURE 20).”
Quote in the paperSubstantial claim- Rests on an assumption: In the CA1 hippocampus, excitatory afferents of both intrahippocampal and subcortical origins target both excitatory and inhibitory neurons.
- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
GABABR postsynaptic potentials/currents have been identified in numerous interneuron subtypes.
“GABABR postsynaptic potentials/currents have been identified in numerous interneuron subtypes (115, 116, 137, 578, 622, 811).”
Quote in the paperNot a substantial claim0 of 6 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
When inhibition and excitation arrived at the same dendritic compartment, inhibition caused a rightward shift in the firing rate function related to excitatory conductance.
“Of interest, they observed that when inhibition and excitation arrived at the same dendritic compartment, inhibition caused a rightward shift in the firing rate function related to excitatory conductance (FIGURE 19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [924] source
Not checked in the free run.
- Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
NGFCs, by virtue of their ability to elicit volume transmission, are a major source of GABA that culminates in GABABR activation.
“NGFCs, by virtue of their ability to elicit volume transmission (see sect. IVL3), are a major source of GABA that culminates in GABABR activation.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Recently CCK-expressing interneurons have been implicated in this proconvulsant phenomenon at least in CA3.
“Again, the interneuron subtype(s) involved remains a mystery, but recently CCK-expressing interneurons have been implicated in this proconvulsant phenomenon at least in CA3 (290).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [290] source
Not checked in the free run.
- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
NMDAR-dependent LTP of excitatory inputs onto CA1 pyramidal cells and dentate gyrus granule cells is sensitive to a concomitant presynaptic GABABR-mediated decrease of GABA release resulting in disinhibition of pyramidal cells and enhanced NMDAR activation.
“Intriguingly, NMDAR-dependent LTP of excitatory inputs onto CA1 pyramidal cells and dentate gyrus granule cells is sensitive to a concomitant presynaptic GABABR-mediated decrease of GABA release resulting in disinhibition of pyramidal cells and enhanced NMDAR activation (255, 810, 939).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisenone given§ C. GABAB Receptor-Mediated Inhibition
Inhibitory inputs are made onto almost all portions of the dendritic tree as well as the perisomatic regions including the axon initial segment.
“In contrast, as stated above, inhibitory inputs are made onto almost all portions of the dendritic tree as well as the perisomatic regions including the axon initial segment.”
Quote in the paperSubstantial claim - Premisenone given§ C. GABAB Receptor-Mediated Inhibition
Activation of postsynaptic GABABRs and subsequent direct G protein interaction with GIRK (Kir3) channels predominantly results in membrane hyperpolarization inhibiting neural excitability.
“Activation of postsynaptic GABABRs and subsequent direct G protein interaction with GIRK (Kir3) channels predominantly results in membrane hyperpolarization inhibiting neural excitability.”
Quote in the paperNot a substantial claim - Premisenone given§ C. GABAB Receptor-Mediated Inhibition
Activation of presynaptic GABABRs on various interneurons results in negative modulation of transmission of varying degrees due to activation of GIRK channels and/or inhibition of voltage-gated calcium channels coupled to vesicular release.
“Activation of presynaptic GABABRs on various interneurons results in negative modulation of transmission of varying degrees due to activation of GIRK channels and/or inhibition of voltage-gated calcium channels coupled to vesicular release.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
CCK-containing interneurons can also play a prominent role in providing feedforward inhibition driven by perforant path and Schaffer collateral inputs to CA1 pyramidal cells.
“Recently, Basu et al. (68) challenged the narrow hypothesis that PVBCs are the main providers of feedforward inhibition and demonstrated that CCK-containing interneurons can also play a prominent role in providing feedforward inhibition driven by perforant path and Schaffer collateral inputs to CA1 pyramidal cells (see also Ref. 1165).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
In this scenario, NGFCs present a novel, nonspecific form of blanket inhibition.
“In this scenario NGFCs would present a novel, nonspecific form of blanket inhibition.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Certain forms of inhibition are promiscuous and less selective in downstream targeting than initially thought.
“However, recent evidence suggests that certain forms of inhibition are promiscuous and less selective in downstream targeting than initially thought (331, 552, 876, 918).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
VIP-containing interneurons provide a mechanism for lateral disinhibition, i.e., inhibition of inhibitory interneurons, which allows principal cells temporary relief from inhibitory control.
“VIP-containing interneurons therefore provide a mechanism for lateral disinhibition, i.e., inhibition of inhibitory interneurons, which allow principal cells temporary relief from inhibitory control.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
In most cortical networks, the dynamic between excitatory and inhibitory inputs is strongly modulated by short-term plasticity of the respective components, such that progressive changes in the excitation:inhibition ratio result in progressive degradation of the excitation and inhibition balance.
“In most cortical networks, the dynamic between excitatory and inhibitory inputs is strongly modulated by the short-term plasticity properties of the respective components, such that progressive changes in the excitation:inhibition ratio results in a progressive degradation of the excitation and inhibition balance (372, 404).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Activation of VIP-containing interneurons in vivo makes "local and transient holes in the inhibitory blanket" provided by SST-containing interneurons, thereby allowing patterns of principal neuron activation to propagate within specific networks.
“Karnani et al. (553) rather elegantly show that activation of VIP-containing interneurons in vivo makes “local and transient holes in the inhibitory blanket” provided by SST-containing interneurons, thereby allowing patterns of principal neuron activation to propagate within specific networks.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [553] source
Not checked in the free run.
- Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Many interneuron subtypes likely contribute in discrete ways to enforce different aspects of feedforward inhibitory control over both principal and interneuron targets.
“Given the surprising number of interneurons whose cell bodies and dendrites occupy space in the CA1 s.r. and can therefore be targeted by both intra- and extrahippocampal afferents, it is highly likely that many interneuron subtypes contribute in discrete ways to enforce different aspects of feedforward inhibitory control over both principal and interneuron targets.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Such an arrangement would ensure that individual or small groups of interneurons target overlapping domains to globally inhibit large numbers of pyramidal cells within their vicinity, diminishing excitatory output.
“Such an arrangement would ensure that individual or small groups of interneurons would target overlapping domains to globally inhibit large numbers of pyramidal cells within their vicinity, thus diminishing excitatory output.”
Quote in the paperNot a substantial claim - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Slowly facilitating excitatory input onto a different population of "late persistent" interneurons recruits dendritic inhibition onto CA1 pyramidal cells.
“In contrast, slowly facilitating excitatory input onto a different population of “late persistent” interneurons recruits dendritic inhibition onto CA1 pyramidal cells.”
Quote in the paperSubstantial claim - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
In CA3 circuits, mossy fiber synapses onto CA3 pyramidal cells provide a strong monosynaptic drive that demonstrates unusually strong facilitation in response to repetitive stimulation.
“In contrast in CA3 circuits, mossy fiber synapses onto CA3 pyramidal cells provide a strong monosynaptic drive that demonstrates unusually strong facilitation in response to repetitive stimulation (538, 641).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Recurrent inhibition onto CA1 pyramidal cells occurs via a dynamic rerouting of inhibitory drive that commences via perisomatic inhibitory input followed by delayed primarily dendritic inhibition.
“Pouille and Scanziani (923) provided the first demonstration that recurrent inhibition onto CA1 pyramidal cells occurs via a dynamic rerouting of inhibitory drive that commences via perisomatic inhibitory input followed by a delayed primarily dendritic inhibition.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [923] source
Not checked in the free run.
- Interpretationcitation§ C. GABAB Receptor-Mediated Inhibition
The output of principal cells is differentially influenced by distinct inhibitory interneuron subpopulations via feedback inhibitory control of spiking activity.
“The output of principal cells is similarly differentially influenced by distinct inhibitory interneuron subpopulations via feedback inhibitory control of spiking activity.”
Quote in the paperSubstantial claim- Rests on an assumption: The output features of principal cells, spike frequency and timing, are critical for correct cortical functioning and are regulated by recurrent excitatory drive onto interneurons that then target the same principal cell populations.
- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Trains of action potentials from CA1 pyramidal cells drive excitation onto two populations of interneurons termed "onset transient" and "late persistent" interneurons.
“Trains of action potentials from CA1 pyramidal cells drive excitation onto two populations of interneurons termed “onset transient” and “late persistent” interneurons (923).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [923] source
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- Premisecitation§ VIII. ENDOCANNABINOIDS
CB1R expression in hippocampal interneurons shows remarkable selectivity for the CCK-expressing subtypes.
“In fact, CB1R expression in hippocampal interneurons shows a remarkable selectivity for the CCK-expressing subtypes (559).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [559] source
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- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
Neocortical PV- and SST-containing interneurons indiscriminately target virtually all principal cells within a 200-μm radius of their cell body, providing "blanket inhibition."
“Using a combination of optogenetics, high-resolution imaging, and electrophysiological techniques, Yuste and colleagues (552) found that neocortical PV- and SST-containing interneurons indiscriminately target virtually all principal cells within a 200-μm radius of their cell body, to provide what has been termed “blanket inhibition.””
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [552] source
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- Premisecitation§ C. GABAB Receptor-Mediated Inhibition
This differential inhibitory input motif is shared across many cortical and hippocampal circuits.
“In fact, this is a motif shared across many cortical and hippocampal circuits (257, 372, 403, 404, 922).”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Mossy fiber-driven feedforward inhibition facilitates to maintain a fixed excitatory:inhibitory balance during trains of activity.
“Mossy fiber-driven feedforward inhibition facilitates to maintain a fixed excitatory:inhibitory balance during trains of activity.”
Quote in the paperSubstantial claim - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
Synaptic events with rapid kinetics exhibiting short-term depression in response to trains of action potentials drive the early-onset transient form of perisomatic inhibition, presumably primarily via PV-containing interneurons back onto CA1 pyramidal cells.
“Synaptic events with rapid kinetics exhibiting short-term depression in response to trains of action potentials drive the early-onset transient form of perisomatic inhibition, presumably primarily via PV-containing interneurons back onto CA1 pyramidal cells.”
Quote in the paperSubstantial claim - Interpretationreasoning§ C. GABAB Receptor-Mediated Inhibition
As a result of slow facilitation, these interneurons (presumably SST-containing O-LM cells, BiCs and CB1R-positive CCK-containing cells) are engaged in a later inhibitory epoch reflecting an integration mode that drives distal dendritic inhibitory inputs proportional to spike rates late in the series.
“As a result of slow facilitation, these interneurons [presumably SST-containing O-LM cells, BiCs and CB1R-positive CCK-containing cells (404)] are engaged in a later inhibitory epoch reflecting an integration mode that drives distal dendritic inhibitory inputs proportional to spike rates late in the series.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [404] source
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- May combine two claims. 341
- Classified as probably not a substantial claim. 72
- The quote only partly states this claim. 2
May combine two claims.
Premisecitation§ II. ANATOMYPVBCs are estimated to comprise ~14% (~5,530 cells) of CA1 interneurons (1.5% of CA1 neurons).
“PVBCs are estimated to comprise ~14% (~5,530 cells) of CA1 interneurons (1.5% of CA1 neurons) (102).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [102] source
Not checked in the free run.
May combine two claims.
Premisecitation§ II. ANATOMYPV expression is not restricted to AACs, and only 15-50% of neocortical AACs are PV immunopositive depending on cortical region examined.
“However, while PV expression is limited to GABAergic interneurons in the cortex and hippocampus (183, 600), it is not restricted to AACs.”
- Also stated in: § II. ANATOMY · hedged
“Further complicating matters, recent evidence indicates that only 15–50% of neocortical AACs are PV immunopositive depending on cortical region examined (475, 1097).”
Quote in the paperNot a substantial claim0 of 3 sources checked- Also stated in: § II. ANATOMY · hedged
May combine two claims.
Premisecitation§ II. ANATOMYAAC cell somas typically reside within (70%) or immediately adjacent to stratum pyramidale, both in stratum oriens (24%) and stratum radiatum (6%).
“Cell somas typically reside within (70%) or immediately adjacent to the s.p. both in s.o. (24%) and stratum radiatum (s.r.) (6%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [102] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ I. INTRODUCTIONDespite being a minority, hippocampal GABAergic interneurons serve as a major determinant of virtually all aspects of cortical circuit function and regulation.
“Despite being in the minority, this diverse neuronal population serves as a major determinant of virtually all aspects of cortical circuit function and regulation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ I. INTRODUCTIONInterneurons are primarily providers of inhibitory GABAergic synaptic input, utilizing Cl− influx or K+ efflux via GABAA or GABAB receptor activation to transiently hyperpolarize or shunt the cell membrane away from action potential threshold.
“Interneurons are primarily providers of inhibitory GABAergic synaptic input, a physiological role that utilizes Cl− influx or K+ efflux via cognate GABAA or GABAB receptor activation, respectively, to transiently hyperpolarize or shunt the cell membrane away from action potential threshold.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ II. ANATOMYIn CA1, AACs are estimated to represent 15% of PV+ interneurons, with the remainder made up mostly of PV+ basket cells and bistratified cells.
“In CA1, AACs are estimated to represent 15% of PV+ interneurons with the remainder made up mostly of PV+ basket cells (PVBCs) and bistratified cells (BiCs) (discussed below) (74).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [74] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ I. INTRODUCTIONIn a 30-day-old Wistar rat, the total CA1 hippocampal neuronal population is estimated at ~350,000, containing a conservative estimate of ~38,500 inhibitory interneurons.
“In a 30-day-old Wistar rat it has been estimated that the total CA1 hippocampal neuronal population is ~350,000, which contains a conservative estimate of ~38,500 inhibitory interneurons (102).”
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Premisecitation§ II. ANATOMYAxo-axonic cells (AACs) are estimated to make up ~4% (~1,500 cells) of CA1 hippocampal interneurons.
“Axo-axonic cells (AACs) are estimated to make up ~4% (~1,500 cells) of CA1 hippocampal interneurons”
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Premisecitation§ II. ANATOMYPVBCs frequently have large pyramidal shaped or fusiform somas typically residing within (70%) or immediately adjacent to stratum pyramidale, both in stratum oriens (24%) and stratum radiatum (6%).
“PVBCs frequently have large pyramidal shaped or fusiform somas typically residing within (70%) or immediately adjacent to s.p. both in s.o. (24%) and s.r. (6%).”
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Interpretationreasoning§ I. INTRODUCTIONInterneurons regulate single cell excitability, provide well-timed inhibitory input that dictates the temporal window for synaptic excitation and action potential initiation, and synchronize local and distributed cortical circuits to facilitate oscillatory activity across broad frequency domains.
“They play major roles in not only the regulation of single cell excitability, but provide well-timed inhibitory input that dictates the temporal window for synaptic excitation, and subsequent action potential initiation, thus shaping the timing of afferent and efferent information flow.”
- Also stated in: § I. INTRODUCTION · plain
“In addition, they harness and synchronize both local and distributed cortical circuits to facilitate oscillatory activity across broad frequency domains.”
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Interpretationcitation§ II. ANATOMYAACs represent 0.04% of all CA1 neurons assuming interneurons account for 11% of the total neuronal population.
“thus representing 0.04% of all CA1 neurons assuming interneurons account for 11% of the total neuronal population (102)”
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- The authors state this as an assumption: Interneurons account for 11% of the total neuronal population in CA1.
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Premisecitation§ II. ANATOMYBoth hippocampal and neocortical AACs have origins in the medial ganglionic eminence (MGE) with specification driven by the homeodomain transcription factor Nkx2.1.
“Both hippocampal and neocortical AACs have origins in MGE with specification driven by the homeodomain transcription factor Nkx2.1 (1097, 1137, 1218).”
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Premisecitation§ II. ANATOMYA large percentage of neocortical AACs are derived late in gestation (~E15-17) from Nkx2.1-expressing progenitors, contrasting with other MGE-derived interneurons that are generated earlier in gestation (~E9-13).
“Interestingly, a large percentage of neocortical AACs are derived late in gestation (~E15–17) from Nkx2.1-expressing progenitors contrasting with other MGE-derived interneurons that are generated earlier in gestation (~E9–13) (1097).”
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Premisecitation§ II. ANATOMYAACs have mostly aspiny, radially oriented dendrites that frequently span all layers from the alveus to stratum lacunosum moleculare, positioning them to receive excitatory input from all excitatory afferent projections innervating the hippocampal CA1 region.
“Their mostly aspiny, radially oriented dendrites frequently span all layers from the alveus to the s.l.m. with minimal branching in s.r. and prominent tufts in the alveus and s.l.m., positioning them to receive excitatory input from all excitatory afferent projections innervating the hippocampal CA1 region (FIGURE 2A) (135, 582, 676).”
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Premisecitation§ C. Bistratified CellsIndividual CCKBCs contact roughly half as many pyramidal cells as PVBCs (~1,250), and the estimated ratio of PVBC to CCKBC terminals on individual postsynaptic pyramidal cell targets is 1.6:1.
“Individual CCKBCs contact roughly half as many pyramidal cells as PVBCs (~1,250), and it is estimated that the ratio of PVBC to CCKBC terminals on individual postsynaptic pyramidal cell targets is 1.6:1 (102, 340, 654, 1225).”
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Premisecitation§ C. Bistratified CellsBiCs have dense axonal arborizations with fine varicose collaterals split above and below stratum pyramidale, simultaneously innervating both the basal and apical dendritic territories of pyramidal cells in almost equal proportion (~50% in stratum oriens to ~40% in stratum radiatum), and they essentially avoid synapsing with perisomatic domains of principal cells.
“BiCs are named for their dense axonal arborizations with fine varicose collaterals split above and below s.p. simultaneously innervating both the basal and apical dendritic territories of pyramidal cells in almost equal proportion (~50% in s.o. to ~40% in s.r) (FIGURE 3A) (135, 455, 561, 583, 790, 885, 1142).”
- Also stated in: § C. Bistratified Cells · plain
“While axon collaterals sparsely travel through s.p. (~10% of the axon) to connect those in s.o. and s.r., BiCs essentially avoid synapsing with the perisomatic domains of principal cells.”
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Premisecitation§ C. Bistratified CellsBiCs appear to have origin in the MGE with specification driven by the homeodomain transcription factor Nkx2.1 (9% of MGE-derived interneurons).
“Though not extensively investigated, BiCs appear to have origin in the MGE with specification driven by the homeodomain transcription factor Nkx2.1 (9% of MGE-derived interneurons) (1138).”
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- The authors state this as an assumption: MGE-derived interneurons account for ~60% of all CA1 interneurons, with relative contributions of 35/25/40% from PV, somatostatin, and neurogliaform/Ivy interneuron cohorts, respectively.
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Interpretationcitation§ C. Bistratified CellsThe anatomical profile of dentate CCKBCs overlaps with cells originally described as hilar commissural-associational pathway-related interneurons (HICAPs), suggesting that HICAPs and dentate CCKBCs are one and the same.
“This anatomical profile overlaps with cells originally described as hilar commissural-associational pathway-related interneurons (HICAPs; Refs. 461, 1013, 457), suggesting that HICAPs and dentate CCKBCs are one and the same (499).”
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Premisecitation§ C. Bistratified CellsCCKBCs are estimated to comprise roughly 9% (~3,600 cells) of all CA1 hippocampal interneurons (1% of all CA1 neurons).
“Cholecystokinin-expressing basket cells (CCKBCs) are estimated to comprise roughly 9% (~3,600 cells) of all CA1 hippocampal interneurons (1% of all CA1 neurons) (102).”
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Premisecitation§ C. Bistratified CellsBiCs are estimated to make up roughly 6% (~2,200 cells) of CA1 interneurons (0.7% of all CA1 neurons).
“BiCs are estimated to make up roughly 6% (~2,200 cells) of CA1 interneurons (0.7% of all CA1 neurons) (102).”
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Premisecitation§ II. ANATOMYPVBCs have origin in the MGE with specification driven by the homeodomain transcription factor Nkx2.1 (21% of MGE-derived interneurons).
“PVBCs have origin in the MGE with specification driven by the homeodomain transcription factor Nkx2.1 (21% of MGE-derived interneurons, see assumptions above) (147, 575, 1138, 1233).”
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- The authors state this as an assumption: MGE-derived interneurons account for ~60% of all CA1 interneurons, with relative contributions of 35/25/40% from PV, somatostatin, and neurogliaform/Ivy interneuron cohorts, respectively.
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Premisecitation§ II. ANATOMYPV expression in both hippocampus and neocortex is minimal before postnatal day 10 then increases to mature levels between PN12-P30 in rodents.
“Importantly, PV expression in both hippocampus and neocortex is minimal before postnatal day (PN) 10 then increases to mature levels between PN12-P30 in rodents (14, 260, 840).”
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Premisecitation§ C. Bistratified CellsBiCs represent ~25% of PV-expressing hippocampal interneurons and coexpress neuropeptide Y (NPY) and SST, allowing them to be molecularly distinguished from other prominent PV+ interneuron populations.
“BiCs represent ~25% of PV-expressing hippocampal interneurons with prominent immunosignal evident throughout the somatodendritic compartments (74).”
- Also stated in: § C. Bistratified Cells · plain
“However, in contrast to AACs and PVBCs, BiCs coexpress neuropeptide Y (NPY) and SST, allowing them to be molecularly distinguished from the other prominent PV+ interneuron populations (75, 561, 583, 1163).”
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Premisecitation§ II. ANATOMYPVBCs predominantly display mostly aspiny, pyramidal-shaped, or bitufted dendritic trees spanning from the alveus to stratum lacunosum moleculare, positioning them to receive input from all excitatory afferent projections innervating the hippocampal CA1 region.
“PVBCs predominantly display mostly aspiny, pyramidal-shaped, or bitufted dendritic trees spanning from the alveus to s.l.m., positioning them to receive input from all excitatory afferent projections innervating the hippocampal CA1 region (FIGURE 2C) (135, 768, 1014).”
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Premisereasoning§ II. ANATOMYPresently there is no genetic strategy that allows for selective targeting and manipulation of PVBCs, and PV-Cre driver lines additionally exhibit recombination in AACs and some PV-expressing dendrite targeting interneuron populations.
“Presently there is no genetic strategy that allows for selective targeting and manipulation of PVBCs.”
- Also stated in: § II. ANATOMY · plain
“Though PV-Cre driver lines allow genetic access to PVBCs, these lines will additionally exhibit recombination in AACs and some PV-expressing dendrite targeting interneuron populations (see below).”
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Premisecitation§ II. ANATOMYMature PVBCs characteristically express PV, which can be detected throughout the somatodendritic and axonal compartments, and their perisomatic targeting nerve terminals express synaptotagmin 2.
“As the name implies, mature PVBCs characteristically express PV, which can be detected throughout the somatodendritic and axonal compartments.”
- Also stated in: § II. ANATOMY · plain
“Perisomatic targeting nerve terminals of mature PVBCs also express, and immunocytochemically label for, synaptotagmin 2 (386, 1030).”
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Premisecitation§ II. ANATOMYPVBCs are estimated to represent ~60% of all PV-containing interneurons within CA1.
“PVBCs are estimated to represent ~60% of all PV-containing interneurons within CA1 (74).”
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Premisecitation§ C. Bistratified CellsNot all CCK immunoreactive neurons are CCKBCs, as CCK can also be detected in glutamatergic principal cell subsets and additional subpopulations of dendrite targeting interneurons.
“However, not all CCK immunoreactive neurons are CCKBCs, as CCK can also be detected in glutamatergic principal cell subsets (1096, 494) and additional subpopulations of dendrite targeting interneurons (352, 1036).”
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Premisecitation§ II. ANATOMYIndividual PVBCs contact up to 2,500 pyramidal cells with an average of 6 synapses onto each one.
“Individual PVBCs contact up to 2,500 pyramidal cells with an average of 6 synapses onto each one (102, 340, 352, 1014).”
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Premisecitation§ II. ANATOMYPVBC axons form basketlike dense pericellular arrays of synaptic boutons primarily innervating the soma and proximal dendrites of pyramidal cells (99% of output synapses), with a minority of outputs (1%) forming autapses or contacting other interneurons.
“The axon emerges from the soma or a primary dendrite and ultimately gives rise to large numbers of collaterals forming basketlike dense pericellular arrays of synaptic boutons primarily innervating the soma and proximal dendrites of pyramidal cells (99% of output synapses), with a minority of outputs (1%) forming autapses or contacting other interneurons (FIGURE 2, C and D) (102, 211, 884, 1014).”
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Premisecitation§ C. Bistratified CellsWhile the majority of CCKBC somas reside within stratum radiatum, with a significant concentration at the stratum radiatum/stratum lacunosum moleculare border, substantial numbers can also be found in stratum pyramidale and stratum oriens.
“While the majority of CCKBC somas reside within s.r., with a significant concentration at the s.r/s.l.m. border, substantial numbers can also be found in s.p. and s.o. (224, 258, 340, 584, 654, 1172).”
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Premisecitation§ C. Bistratified CellsThe cell bodies of most BiCs reside within stratum pyramidale (70%) and widely extend multipolar dendrites throughout stratum oriens and stratum radiatum.
“The cell bodies of most BiCs cells reside within s.p. (70%) and widely extend multipolar dendrites throughout s.o. and s.r. (FIGURE 3A) (135, 455, 561, 583, 790, 885, 1142).”
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Premisecitation§ II. ANATOMYThe Nkx2.1 lineage also gives rise to dendrite targeting somatostatin (SST)-expressing interneurons, and thus use of Nkx2.1-Cre lines in isolation results in recombination within a wide variety of perisomatic and dendrite targeting interneurons.
“However, the Nkx2.1 lineage also gives rise to dendrite targeting somatostatin (SST)-expressing interneurons, and thus use of Nkx2.1-Cre lines in isolation will result in recombination within a wide variety of perisomatic and dendrite targeting interneurons (147, 339, 1138, 1233, 1235).”
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Premisecitation§ C. Bistratified CellsDendrite targeting CCK-expressing interneurons are also found in the neocortex, most notably the vertically oriented bitufted double bouquet cells with ascending and descending tight radial axonal bundles targeting principal cell dendritic shafts and spines.
“Dendrite targeting CCK-expressing interneurons are also found in the neocortex, most notably the vertically oriented bitufted double bouquet cells with ascending and descending tight radial axonal bundles targeting principal cell dendritic shafts and spines (263, 355, 556, 569, 1034, 1085, 1150).”
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Premisecitation§ C. Bistratified CellsCCKBCs are considered to parse into at least two subtypes: those that coexpress vasoactive intestinal peptide (VIP) and those that coexpress vesicular glutamate transporter 3 (VGluT3), though neither marker is specific on its own for CCKBCs and a substantial proportion of CCKBCs express neither.
“Molecularly, CCKBCs are considered to parse into at least two subtypes: those that coexpress vasoactive intestinal peptide (VIP) and those that coexpress vesicular glutamate transporter 3 (VGluT3), though again neither of these markers is specific on their own for CCKBCs and a substantial proportion of CCKBCs express neither of them (5, 102, 1031).”
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Premisecitation§ C. Bistratified CellsCCK-expressing dendrite targeting interneurons largely reside in s.r., with some tendency to concentrate at the s.r./s.l.m. border.
“CCK-expressing dendrite targeting interneurons together comprise between 3 and 5% (~1,500 cells) of CA1 interneurons (~0.4% of all CA1 neurons), largely reside in s.r., with some tendency to concentrate at the s.r./s.l.m. border.”
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Premisecitation§ C. Bistratified CellsAdditional molecular markers commonly associated with hippocampal and neocortical CCK-expressing dendrite targeting interneurons are calbindin (CB) (hippocampus and neocortex), calretinin (CR) (neocortex), and VIP (neocortex), though none of these markers is specific for or ubiquitously expressed by CCK-expressing dendrite targeting interneurons.
“Additional molecular markers commonly associated with hippocampal and neocortical CCK-expressing dendrite targeting interneurons are calbindin (CB) (hippocampus and neocortex), calretinin (CR) (neocortex), and VIP (neocortex), though none of these markers is specific for or ubiquitously expressed by CCK-expressing dendrite targeting interneurons (224, 556, 569, 584, 611, 612).”
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Premisecitation§ C. Bistratified CellsCCKBCs can be genetically targeted using CCK-Cre driver mice; however, additional CCK-expressing interneurons and even some glutamatergic principal cell subsets will also exhibit recombination.
“CCKBCs can be genetically targeted using CCK-Cre driver mice; however, additional CCK-expressing interneurons and even some glutamatergic principal cell subsets will also exhibit recombination (68, 1095, 1096).”
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Premisecitation§ C. Bistratified CellsADIs are similar to SCAs but preferentially innervate the main apical shaft of pyramidal cells avoiding oblique and basal dendrites.
“Apical dendrite targeting interneurons (ADIs) are similar to SCAs but preferentially innervate the main apical shaft of pyramidal cells avoiding oblique and basal dendrites (584).”
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Interpretationcitation§ C. Bistratified CellsDespite weak GABABR immunoreactivity in PVBCs compared with CCKBCs, presynaptic release from both terminal subsets is functionally depressed by GABABR activation.
“Thus, despite weak GABABR immunoreactivity in PVBCs compared with CCKBCs (1024), presynaptic release from both terminal subsets is functionally depressed by GABABR activation.”
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Premisecitation§ C. Bistratified CellsCCK-expressing dendrite targeting interneurons generally extend multipolar dendrites spanning all layers, though horizontally oriented dendritic arbors mostly confined to s.r. have also been observed.
“They generally extend multipolar dendrites spanning all layers, though horizontally oriented dendritic arbors mostly confined to s.r. have also been observed (181, 224, 452, 584, 654, 885, 1172).”
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Premisecitation§ C. Bistratified CellsAll CCK-expressing dendrite targeting cells dominantly target principal cell postsynaptic targets with ~6 synapses per connection.
“All CCK-expressing dendrite targeting cells dominantly target principal cell postsynaptic targets with ~6 synapses per connection; however, a minority of terminals (~8%) innervate other interneurons (102, 224, 584, 1172).”
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Premisecitation§ C. Bistratified CellsWhile O-LMs with classic horizontally oriented dendrites restricted to s.o. can be found in CA3, there are additional populations with multipolar dendrites extending across all strata except s.l.m.
“While O-LMs with classic horizontally oriented dendrites restricted to s.o. can be found in CA3, there are additional populations with multipolar dendrites extending across all strata except s.l.m. (352, 441, 442).”
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Premisecitation§ C. Bistratified CellsThe number of branches ascending through s.p. and s.r. is variable (typically between 1 and 5), but all branches generally continue to s.l.m. before collateralizing into a dense axonal cloud with fine varicosities dominantly innervating pyramidal cell spines and dendritic shafts.
“The number of branches ascending through s.p. and s.r. is variable (typically between 1 and 5), but all branches generally continue to s.l.m. before collateralizing into a dense axonal cloud with fine varicosities dominantly innervating pyramidal cell spines and dendritic shafts (e.g., compare cell recoveries from References 324, 561, 642, 721, 768).”
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Premisecitation§ C. Bistratified CellsIndividual O-LMs are estimated to contact around 1,450 pyramidal cells with an average of 10 synapses per connection.
“Individual O-LMs are estimated to contact around 1,450 pyramidal cells with an average of 10 synapses per connection (102, 1014).”
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Interpretationreasoning§ C. Bistratified CellsThe restriction of horizontally oriented O-LM soma and spiny dendrites within s.o. and the alveus dictates that the dominant source of excitatory recruitment is from CA1 pyramidal cell collaterals while the preferential axonal targeting to s.l.m. then distributes inhibition back to the distal apical dendritic tufts of CA1 pyramidal cells to gate excitatory input from the entorhinal cortex and reni
“Indeed, the restriction of horizontally oriented O-LM soma and spiny dendrites within s.o. and the alveus dictates that the dominant source of excitatory recruitment is from CA1 pyramidal cell collaterals while the preferential axonal targeting to s.l.m. then distributes inhibition back to the distal apical dendritic tufts of CA1 pyramidal cells to gate excitatory input from the entorhinal cortex”
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Premisecitation§ C. Bistratified CellsSST is not restricted to these cell populations, and in the hippocampus, O-LMs are estimated to comprise only 40% of SST-expressing interneurons.
“However, SST is not restricted to these cell populations, and in the hippocampus, O-LMs are estimated to comprise only 40% of SST-expressing interneurons (102, 324, 716, 862, 1154).”
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Premisecitation§ C. Bistratified CellsReelin is frequently coexpressed with SST in O-LM and Martinotti cells, but is not selective for or necessarily comprehensively expressed by these interneurons.
“Reelin is frequently coexpressed with SST in O-LM and Martinotti cells, but is not selective for or necessarily comprehensively expressed by these interneurons (203, 367, 651, 796, 899).”
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Premisecitation§ C. Bistratified CellsAfter emerging from the soma or a proximal dendrite, ~7% of an O-LM axon remains in s.o. while greater than 90% is targeted to s.l.m.
“After emerging from the soma or a proximal dendrite, ~7% of an O-LM axon remains in s.o. while greater than 90% is targeted to s.l.m. (1014).”
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Premisecitation§ C. Bistratified CellsVGluT3 expression was originally described as being limited to CCKBCs, it has also been detected in ADIs.
“While VGluT3 expression was originally described as being limited to CCKBCs (1031), it has also been detected in ADIs (584).”
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Premisecitation§ C. Bistratified CellsWhile limited evidence supports NPY expression in morphologically identified Martinotti and HIPP cells, anatomically identified O-LMs repeatedly fail to immunostain for NPY.
“However, while limited evidence supports NPY expression in morphologically identified Martinotti and HIPP cells (352, 549, 612, 716, 1192), anatomically identified O-LMs repeatedly fail to immunostain for NPY (561, 862, 344).”
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Premisecitation§ C. Bistratified CellsO-LMs express PV, albeit at significantly lower levels than AACs/PVBCs/BiCs, while PV and SST are considered mutually exclusive in the neocortex.
“On the other hand, O-LMs express PV, albeit at significantly lower levels than AACs/PVBCs/BiCs, while PV and SST are considered mutually exclusive in the neocortex (324, 344, 561, 568, 582, 721, 1142, 1237).”
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Premisecitation§ C. Bistratified CellsIn the hippocampus, preferential targeting for O-LMs has been reported using a driver line based on nicotinic acetylcholine receptor α2 subunit promoter activity (Chrna2-Cre mice).
“In the hippocampus, preferential targeting for O-LMs has been reported using a driver line based on nicotinic acetylcholine receptor α2 subunit promoter activity (Chrna2-Cre mice) (649, 787).”
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Premisecitation§ C. Bistratified CellsA subset of hippocampal SST-expressing interneurons, including a subpopulation of O-LMs, expresses 5-HT3ARs consistent with developmental origins in the CGE (O-LMs comprise 4% of CGE-derived interneurons based on assumptions outlined above combined with the fact that O-LMs represent 40% of SST interneurons).
“Interestingly, a subset of hippocampal SST-expressing interneurons, including a subpopulation of O-LMs, expresses serotonin 3A receptors (5-HT3ARs) consistent with developmental origins in the CGE (O-LMs comprise 4% of CGE-derived interneurons based on assumptions outlined above combined with the fact that O-LMs represent 40% of SST interneurons) (102, 203, 651, 1179).”
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Premisecitation§ C. Bistratified CellsMartinotti cells and 5-HT3AR-lacking O-LM cells arise from MGE progenitors with specification driven by the homeodomain transcription factor Nkx2.1 (10% of MGE-derived hippocampal interneurons based on assumptions outlined above combined with the fact that O-LMs represent 40% of SST interneurons).
“In contrast, Martinotti cells and 5-HT3AR-lacking O-LM cells arise from MGE progenitors with specification driven by the homeodomain transcription factor Nkx2.1 (10% of MGE-derived hippocampal interneurons based on assumptions outlined above combined with the fact that O-LMs represent 40% of SST interneurons) (102, 203, 651, 794, 1042, 1134, 1138, 1213).”
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Interpretationreasoning§ C. Bistratified CellsThus hippocampal SST-expressing interneurons, including O-LMs, appear to have dual MGE and CGE origins while neocortical SST expressing interneurons arise from the MGE only.
“Thus hippocampal SST-expressing interneurons, including O-LMs, appear to have dual MGE and CGE origins while neocortical SST expressing interneurons arise from the MGE only.”
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Premisecitation§ C. Bistratified CellsIvCs are closely related to NGFCs and are estimated to be the largest cohort of hippocampal interneurons making up almost a quarter (23%, 8,800 cells) of the entire CA1 interneuron population (2.5% of all CA1 neurons).
“Ivy cells (IvCs) are closely related to NGFCs and are estimated to be the largest cohort of hippocampal interneurons making up almost a quarter (23%, 8,800 cells) of the entire CA1 interneuron population (2.5% of all CA1 neurons) (102, 366, 1137).”
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Premisecitation§ C. Bistratified CellsNGFC dendrites and axons can also cross the hippocampal fissure into the molecular layer of the dentate gyrus and penetrate into superficial s.r., indicating that CA1 NGFC recruitment and distribution of inhibition extend beyond s.l.m.
“However, NGFC dendrites and axons can also cross the hippocampal fissure into the molecular layer of the dentate gyrus and penetrate into superficial s.r., indicating that CA1 NGFC recruitment and distribution of inhibition extend beyond s.l.m. (367, 550, 926, 927).”
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Premisecitation§ C. Bistratified CellsNGFCs exhibit a remarkably high degree of chemical and electrical connectivity with each other and promiscuously with additional non-NGFC interneuron subtypes allowing individual NGFCs to extend their influence well beyond their local dense axonal cloud through disinhibition and coordination of inhibitory networks.
“Interestingly, NGFCs exhibit a remarkably high degree of chemical and electrical connectivity with each other and promiscuously with additional non-NGFC interneuron subtypes allowing individual NGFCs to extend their influence well beyond their local dense axonal cloud through disinhibition and coordination of inhibitory networks (926, 1017, 1280, 1281).”
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Premisecitation§ C. Bistratified CellsIn the dentate gyrus, NGFCs frequently reside in the outer molecular layer where they also exhibit dense axonal clouds that can penetrate the hippocampal fissure to invade the CA1 and subiculum subfields.
“In the dentate gyrus, NGFCs frequently reside in the outer molecular layer where they also exhibit dense axonal clouds that can penetrate the hippocampal fissure to invade the CA1 and subiculum subfields (48, 184).”
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Premisecitation§ C. Bistratified CellsThe cloud of GABA generated from NGFC release can also activate presynaptic GABABR to mediate homosynaptic and heterosynaptic depression of GABAergic and glutamatergic release sometimes with remarkable target cell specificity.
“In addition, the cloud of GABA generated from NGFC release can also activate presynaptic GABABR to mediate homosynaptic and heterosynaptic depression of GABAergic and glutamatergic release (48, 858, 859, 926, 927) sometimes with remarkable target cell specificity (204).”
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Premisenone given§ C. Bistratified CellsThe axon arises from the soma or a primary dendrite and extensively collateralizes giving rise to a remarkably dense local fine axonal plexus.
“The axon arises from the soma or a primary dendrite and extensively collateralizes giving rise to a remarkably dense local fine axonal plexus (FIGURE 3D).”
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Premisenone given§ C. Bistratified CellsIn both the hippocampus and neocortex, NPY and reelin are likely expressed by all NGFCs, although neither of these markers or their combination is selective for NGFCs.
“In both the hippocampus and neocortex, NPY and reelin are likely expressed by all NGFCs, although neither of these markers or their combination is selective for NGFCs.”
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Premisecitation§ C. Bistratified CellsDentate gyrus NGFCs have been found in the hilus near s.g.
“In addition, dentate gyrus NGFCs have been found in the hilus near s.g. (751).”
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Premisecitation§ C. Bistratified CellsWhile neocortical NGFCs can be found throughout all layers, they are particularly enriched in supragranular layers and form a major constituent cell population in L1.
“While neocortical NGFCs can be found throughout all layers, they are particularly enriched in supragranular layers and form a major constituent cell population in L1 (564, 858, 1017, 1074, 1086, 1134).”
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Interpretationreasoning§ C. Bistratified CellsBased on these features, ISI-2s appear to provide a disinhibitory network that largely overlaps with that of ISI-1s in the CA3 Schaffer collateral termination zone of CA1 pyramidal cell apical dendrites, but that is preferentially recruited by entorhinal and reuniens inputs.
“Based on these features, ISI-2s appear to provide a disinhibitory network that largely overlaps with that of ISI-1s in the CA3 Schaffer collateral termination zone of CA1 pyramidal cell apical dendrites, but that is preferentially recruited by entorhinal and reuniens inputs.”
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Premisenone given§ C. Bistratified Cells~50% of the bipolar ISI-2s coexpress CR with VIP while ISI-2s with dendrites restricted to s.l.m. do not express CR.
“Further complication in parsing this subpopulation from ISI-1s is the fact ~50% of the bipolar ISI-2s coexpress CR with VIP while ISI-2s with dendrites restricted to s.l.m. do not express CR.”
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Premisecitation§ C. Bistratified CellsType 2 ISIs (ISI-2s) are VIP-expressing interneurons with cell somas typically found at the border of s.r. and s.l.m.
“Type 2 ISIs (ISI-2s) are VIP-expressing interneurons with cell somas typically found at the border of s.r. and s.l.m. (5, 6).”
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Premisenone given§ C. Bistratified CellsLike ISI-1s, the VIP-expressing terminals of ISI-2s preferentially form multiple synaptic contacts on the somas and dendrites of CB-expressing dendrite targeting interneurons (i.e., CCK-expressing dendrite targeting interneurons) and also innervate other VIP-expressing interneurons (likely CCKBCs and other ISI-2s or ISI-3s).
“Like ISI-1s, the VIP-expressing terminals of ISI-2s preferentially form multiple synaptic contacts on the somas and dendrites of CB-expressing dendrite targeting interneurons (i.e., CCK-expressing dendrite targeting interneurons) and also innervate other VIP-expressing interneurons (likely CCKBCs and other ISI-2s or ISI-3s, see below) located throughout s.r.”
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Premisenone given§ C. Bistratified CellsThese dentate ISIs are typically bipolar with fusiform cell somas often located in s.g. or in the molecular layer and emit axons that primarily target the dendrites of SST-expressing HIPP cells located in the hilus.
“These dentate ISIs are typically bipolar with fusiform cell somas often located in s.g. or in the molecular layer and emit axons that primarily target the dendrites of SST-expressing HIPP cells located in the hilus.”
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Premisecitation§ C. Bistratified CellsIn the hippocampus such ISIs are estimated to comprise almost 20% of all CA1 interneurons (2.2% of all CA1 neurons) and are separable into three subsets based on unique morphological and neurochemical signatures.
“In the hippocampus such ISIs are estimated to comprise almost 20% of all CA1 interneurons (2.2% of all CA1 neurons) and are separable into three subsets based on unique morphological and neurochemical signatures outlined below (102, 186, 352, 353).”
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Premisecitation§ C. Bistratified CellsThis disinhibitory motif is also common to the neocortex where a majority of vertically oriented bipolar VIP and CR coexpressing interneurons reside in layer2/3 and emit axons that preferentially innervate dendrite targeting SST expressing interneurons within the same column.
“This disinhibitory motif is also common to the neocortex where a majority of vertically oriented bipolar VIP and CR coexpressing interneurons reside in layer2/3 and emit axons that preferentially innervate dendrite targeting SST expressing interneurons within the same column (168, 363, 425, 475, 553, 652, 906, 928, 1046, 1134, 1270).”
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Premisenone given§ C. Bistratified CellsThe smooth dendritic trees of ISI-1s arborize most extensively within s.r. but also infiltrate all other strata.
“The smooth dendritic trees of ISI-1s arborize most extensively within s.r. but also infiltrate all other strata.”
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Premisecitation§ C. Bistratified CellsInitially, such ISIs were anatomically identified and characterized through immunostaining for CR or VIP with correlated light microscopy and ultrastructural analyses revealing that the major postsynaptic elements targeted by CR and VIP terminals were dendrites and somas of dendrite targeting GABAergic cells.
“Initially, such interneuron selective interneurons (ISIs) were anatomically identified and characterized through immunostaining for CR or VIP with correlated light microscopy and ultrastructural analyses revealing that the major postsynaptic elements targeted by CR and VIP terminals were dendrites and somas of dendrite targeting GABAergic cells (5, 6, 425, 439, 449, 1046).”
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Premisenone given§ C. Bistratified CellsThe axons of ISI-2s descend in the opposite direction to ramify in a mostly radial orientation throughout s.r. giving rise to a number of fine branches again with highly uneven terminal distributions.
“The axons of ISI-2s descend in the opposite direction to ramify in a mostly radial orientation throughout s.r. giving rise to a number of fine branches again with highly uneven terminal distributions.”
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Premisecitation§ C. Bistratified CellsRecent functional investigations have confirmed O-LMs as the preferred target of ISI-3s and additionally revealed less frequent connections between ISI-3s with other interneurons including BiCs and PVBCs but not with CA1 pyramidal neurons.
“Recent functional investigations have confirmed O-LMs as the preferred target of ISI-3s and additionally revealed less frequent connections between ISI-3s with other interneurons including BiCs and PVBCs but not with CA1 pyramidal neurons (185, 1145).”
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Premisenone given§ C. Bistratified CellsThe preferred targets of ISI-1s are CB-expressing dendrite targeting interneurons (likely SCAs, PPAs, and CCK-expressing interneurons described above), other CR-expressing ISI-1s, and VIP-expressing CCKBCs.
“The preferred targets of ISI-1s are CB-expressing dendrite targeting interneurons (likely SCAs, PPAs, and CCK-expressing interneurons described above), other CR-expressing ISI-1s, and VIP-expressing CCKBCs.”
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Interpretationreasoning§ C. Bistratified CellsThese braidlike structures connect clusters of ~15 ISI-1s and likely serve to synchronize their activity through electrical and chemical synapses.
“These braidlike structures connect clusters of ~15 ISI-1s and likely serve to synchronize their activity through electrical and chemical synapses.”
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Premisecitation§ C. Bistratified CellsIvCs are named for the English ivy-like appearance of their axons which branch profusely close to their origin giving rise to a dense cloud of fine thin collaterals with frequent small en passant boutons much like those of NGFCs but targeting more proximal oblique and basal CA1 pyramidal cell dendrites.
“IvCs are named for the English ivy-like appearance of their axons which branch profusely close to their origin giving rise to a dense cloud of fine thin collaterals with frequent small en passant boutons much like those of NGFCs but targeting more proximal oblique and basal CA1 pyramidal cell dendrites (FIGURE 3E) (366).”
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Premisecitation§ C. Bistratified CellsIn contrast to NGFCs, IvC somas avoid s.l.m. and are dominantly found in and around s.p. but also populate s.o. and s.r. to lesser extents.
“In contrast to NGFCs, IvC somas avoid s.l.m. and are dominantly found in and around s.p. but also populate s.o. and s.r. to lesser extents (366, 367, 1032, 1075, 1137).”
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Premisereasoning§ C. Bistratified CellsThe aspiny multipolar dendrites of IvCs are less compact than those of NGFCs and frequently extend beyond their axonal span to largely inhabit s.o. and s.r., positioning them for feedforward recruitment by CA3 Schaffer collateral inputs and also for feedback recruitment by CA1 pyramidal cell collaterals.
“The aspiny multipolar dendrites of IvCs are less compact than those of NGFCs and frequently extend beyond their axonal span to largely inhabit s.o. and s.r., positioning them for feedforward recruitment by CA3 Schaffer collateral inputs and also for feedback recruitment by CA1 pyramidal cell collaterals (FIGURE 3E).”
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Interpretationcitation§ C. Bistratified CellsThe recent development of tools that allow for an intersectional approach reliant upon VIP and CR coexpression offers the potential to significantly refine genetic targeting of ISIs.
“The recent development of tools that allow for an intersectional approach reliant upon VIP and CR coexpression (i.e., VIP-flp with CR-Cre driver lines) offers the potential to significantly refine genetic targeting of ISIs (475).”
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Premisecitation§ C. Bistratified CellsIn both neocortex and hippocampus, CR- and VIP-expressing ISIs represent subsets of 5-HT3AR-expressing interneurons and have singular origin in the CGE (combined ISIs represent 30% of CGE-derived interneurons based on assumptions outlined above).
“In both neocortex and hippocampus, CR- and VIP-expressing ISIs represent subsets of 5-HT3AR-expressing interneurons and have singular origin in the CGE (combined ISIs represent 30% of CGE-derived interneurons based on assumptions outlined above) (102, 203, 651, 796, 1138, 1179).”
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Premisecitation§ C. Bistratified CellsThese driver lines have been successfully used in a number of recent studies to dissect circuit functions of ISIs in both hippocampus and neocortex.
“Indeed, these driver lines have been successfully used in a number of recent studies to dissect circuit functions of ISIs in both hippocampus and neocortex (363, 553, 652, 906, 908, 1145, 1270).”
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Interpretationreasoning§ C. Bistratified CellsIn the neocortex, the expression of CR by subsets of SST expressing Martinotti cells could complicate interpretation of studies using CR-Cre driver mice.
“Similarly in the neocortex, the expression of CR by subsets of SST expressing Martinotti cells could complicate interpretation of studies using CR-Cre driver mice.”
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Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINSProx1 is present in the SVZs of all GEs, but its expression is selectively maintained in CGE-derived and downregulated in MGE-derived interneuron precursors.
“while the homeodomain transcription factor Prox1 is present in the SVZs of all GEs, its expression is selectively maintained in CGE-derived, and downregulated in MGE-derived, interneuron precursors”
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Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINSLoss of cyclin D2 results in a 30-40% reduction in PV-expressing neocortical interneurons with no change in SST interneuron numbers.
“loss of the cell cycle regulator cyclin D2, which is enriched within SVZ BPs of the MGE, results in a 30–40% reduction in PV-expressing neocortical interneurons with no change in SST interneuron numbers”
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Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINSCGE interneuronogenesis lags that of the MGE both for initial generation (E12.5 for CGE vs. E9.5 for MGE) and peak generation (E16.5 for CGE vs. E13.5 for MGE).
“CGE interneuronogenesis was demonstrated to lag that of the MGE both for initial (E12.5 for CGE vs. E9.5 for MGE) and peak (E16.5 for CGE vs. E13.5 for MGE) generation”
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Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINSIn mature neocortex and hippocampus, 5-HT3AR-GFP reported cells are GABAergic interneurons that largely overlap (>90%) with those reported by the Mash1-CreER driver line and have minimal overlap with the Nkx2.1 lineage.
“in the mature neocortex and hippocampus, 5-HT3AR-GFP reported cells are GABAergic interneurons that largely overlap (>90%) with those reported by the Mash1-CreER driver line described above, and have minimal overlap, to the populations reported in the Nkx2.1 lineage”
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Premisenone given§ III. DEVELOPMENT AND EMBRYONIC ORIGINSNeocortical NGFCs and SST interneurons have singular origins within the CGE and MGE, respectively.
“neocortical NGFCs and SST interneurons (e.g., Martinotti cells) have singular origins within the CGE and MGE, respectively”
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Premisecitation§ III. DEVELOPMENT AND EMBRYONIC ORIGINSIn the hippocampus, CGE-derived interneurons include CCK-expressing interneurons, ISIs, a subset of NGFCs, and approximately 40% of SST-expressing interneurons.
“In the hippocampus CGE-derived interneurons include CCK-expressing interneurons (CCKBCs, SCAs, ADIs, PPAs), ISIs (VIP and CR expressing), a subset of NGFCs, and ~40% of SST-expressing interneurons (e.g., O-LMs)”
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Premisecitation§ C. The Preoptic AreaMGE progenitors preferentially express Nkx2.1, which must be downregulated in migrating postmitotic cells for them to avoid the striatum and reach the cortex.
“MGE progenitors preferentially express the transcription factor Nkx2.1 (147, 148, 829, 1233), which must be downregulated in migrating postmitotic cells in order for them to avoid the striatum and reach the cortex”
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Premisecitation§ C. The Preoptic AreaThe choice of migratory path appears to be an intrinsic property of cells dependent on their region of origin and ultimate destination, and governed by different transcription factors.
“The choice of migratory path appears to be an intrinsic property of cells dependent on their region of origin and ultimate destination, and governed by different transcription factors”
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Interpretationreasoning§ C. The Preoptic AreaThe POA contributes a minor yet highly diverse population of cortical interneurons, some MGE-like and others CGE-like.
“Thus the POA contributes a minor yet highly diverse population of cortical interneurons some of which are MGE-like while others display more CGE-like mature phenotypes.”
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Premisecitation§ C. The Preoptic AreaCxcr7 regulates the local concentrations of Cxcl12 sensed by Cxcr4 and controls Cxcr4 protein levels.
“Cxcr7 regulates the local concentrations of Cxcl12 sensed by Cxcr4 and controls Cxcr4 protein levels”
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Premisecitation§ C. The Preoptic AreaMGE- and CGE-derived interneurons reach the dorsal telencephalon via separate pathways: MGE-derived cells travel via dorsolateral routes, while CGE-derived cells follow three distinct routes laterally, medially, and caudally.
“MGE- and CGE-derived interneurons reach the dorsal telencephalon via separate pathways: those from the MGE travel via dorsolateral routes while those from the CGE follow three distinct routes laterally, medially, and caudally.”
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Premisecitation§ C. The Preoptic AreaClonally related interneurons disperse widely across the telencephalon, and spatially restricted clusters of interneurons are comprised of cells unrelated by a common progenitor.
“clonally related interneurons disperse widely across the telencephalon and that spatially restricted clusters of interneurons are in fact comprised of cells unrelated by a common progenitor”
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Premisecitation§ C. The Preoptic AreaGABA either promotes or arrests radial migration depending on cell maturity, due to developmental regulation of the chloride gradient.
“GABA either promotes or arrests radial migration dependent on cell maturity. This is due to developmental regulation of the chloride gradient”
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Premisecitation§ C. The Preoptic AreaClonally related sister principal cells are radially aligned in the cortex and preferentially form synaptic connections.
“clonally related sister PCs were found to be radially aligned in the cortex and to preferentially form synaptic connections”
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Interpretationcitation§ C. The Preoptic AreaLoss of reelin signaling does not disrupt interneuron lamination in a cell-autonomous manner; rather, it disrupts principal cell lamination, which in turn instructs interneuron migration.
“Thus loss of reelin signaling does not disrupt interneuron lamination in a cell-autonomous manner; rather, it disrupts PC lamination, which in turn instructs interneuron migration.”
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Premisecitation§ C. The Preoptic AreaIn the cortex, principal cells laminate in an inside-out manner according to their birthdate: early born cells take up residence in deep layers while those born later populate superficial layers.
“In the cortex it is well established that PCs laminate in an inside-out manner according to their birthdate: early born cells take up residence in deep layers while those born later populate the superficial layers”
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Interpretationnone given§ C. The Preoptic AreaAn emerging model proposes that principal cells instruct the radial migration and synaptic connectivity of interneurons.
“an emerging model proposes that PCs instruct their radial migration and synaptic connectivity”
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Premisecitation§ C. The Preoptic AreaIn cortex, MGE-derived cells are biased towards deep layers and CGE-derived cells towards superficial layers.
“In cortex, MGE- and CGE-derived cells are biased towards the deep and superficial layers, respectively”
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Premisecitation§ C. The Preoptic AreaIn the hippocampus, MGE-derived interneurons are biased towards the deeper s.o. and s.p., while CGE-derived interneurons are primarily found in the more superficial s.r. and s.l.m.
“in the hippocampus, MGE-derived interneurons are biased towards the deeper s.o. and s.p., while those from the CGE are primarily found in the more superficial s.r. and s.l.m.”
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Premisecitation§ C. The Preoptic AreaCxcl12 is expressed selectively on the somas of subcerebral projection neurons and Cxcr7 is expressed on the axon terminals of PVBCs.
“Cxcl12 is expressed selectively on the somas of subcerebral projection neurons and Cxcr7 is expressed on the axon terminals of PVBCs”
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Premisecitation§ C. The Preoptic AreaCGE-derived interneurons lack correlation with birth order; their attraction to superficial layers is dominant regardless of birthdate.
“CGE-derived interneurons lack any such correlation with birth order; rather, their attraction to the superficial layers is dominant regardless of birthdate”
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Premisecitation§ C. The Preoptic AreaKCC2 levels increase as interneurons mature, rendering GABAA hyperpolarizing to reduce calcium influx and stop radial migration within the cortex.
“KCC2 levels increase as interneurons mature which renders GABAA hyperpolarizing to reduce calcium influx and stop radial migration within the cortex”
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Premisecitation§ C. The Preoptic AreaIn the reeler mouse model, lamination of principal cells in cortex is inverted and the s.p. of the hippocampus is split in region CA1.
“in the reeler mouse model, in which expression of reelin or associated proteins is disrupted, the lamination of PCs in cortex is inverted and the s.p. of the hippocampus is split in region CA1”
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Premisecitation§ C. The Preoptic AreaGDPs can also be initiated in CA1, where neonatal recurrent excitation is driven almost exclusively by interneurons, and propagate back to CA3.
“GDPs can also be initiated in CA1, where neonatal recurrent excitation is driven almost exclusively by interneurons, and propagate back to CA3”
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Premisecitation§ C. The Preoptic AreaIn the hippocampus, GDPs are most readily initiated in area CA3, where depolarization from local interneurons leads to burst firing among recurrently connected principal cells, followed by propagation to CA1.
“In the hippocampus GDPs are most readily initiated in area CA3, where depolarization from local interneurons leads to burst firing among recurrently connected PCs, followed by propagation to CA1”
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Premiseown data§ C. The Preoptic AreaGDPs occur as rhythmic bouts of reverberating activity within a local circuit lasting hundreds of milliseconds and travel as a wave.
“GDPs occur as rhythmic bouts of reverberating activity within a local circuit lasting hundreds of milliseconds and travel as a wave”
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Premisecitation§ C. The Preoptic AreaIn the neocortex, GDPs emerge a couple of days later than those observed in the hippocampus and are primarily generated in the deep layers.
“In the neocortex, GDPs emerge a couple of days later than those observed in the hippocampus and are primarily generated in the deep layers”
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Premisecitation§ C. The Preoptic AreaBlockade of GABARs alone or optogenetic silencing of interneurons dramatically reduces or abolishes the occurrence of GDPs.
“blockade of GABARs alone or optogenetic silencing of interneurons dramatically reduces or abolishes the occurrence of GDPs”
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Premisecitation§ C. The Preoptic AreaIn principal cells, the earliest synaptic currents detected postnatally are mediated by GABAARs and NMDARs; AMPAR-mediated currents are initially absent and appear later during the first postnatal week.
“In PCs, the earliest synaptic currents detected postnatally are mediated by GABAARs and NMDARs; AMPA receptor (AMPAR)-mediated currents are initially absent, only appearing later during the first postnatal week”
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Premisecitation§ C. The Preoptic AreaPerturbations of GABAergic excitation in vivo disrupt principal cell glutamatergic synaptogenesis, which can be rescued by increased NMDAR-mediated transmission.
“perturbations of GABAergic excitation in vivo disrupt PC glutamatergic synaptogenesis, which can be rescued by increased NMDAR-mediated transmission”
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Premisecitation§ C. The Preoptic AreaEndocannabinoid agonists suppress GDPs while antagonists increase their frequency, strongly implying the participation of CGE-derived CCK-containing interneurons.
“endocannabinoid agonists suppress GDPs while antagonists increase their frequency, strongly implying the participation of CGE-derived CCK-containing interneurons”
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Premisecitation§ C. The Preoptic AreaA subset of interneurons referred to as hub cells are highly interconnected within local hippocampal circuits and powerfully modulate GDPs, with some capable of triggering GDPs on their own.
“a subset of interneurons referred to as hub cells are highly interconnected within local hippocampal circuits and powerfully modulate GDPs, with some capable of triggering GDPs on their own”
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Premisecitation§ C. The Preoptic AreaInterneurons are positioned to promote early network oscillations, which in turn provide depolarization necessary for glutamatergic synapse development via calcium influx through NMDARs.
“interneurons are positioned to promote early network oscillations, which in turn provide depolarization necessary for glutamatergic synapse development via calcium influx through NMDARs”
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Premisecitation§ C. The Preoptic AreaBlocking NKCC1 with bumetanide injections or forcing early overexpression of KCC2 produced similar results.
“Similar results were obtained by blocking NKCC1 with bumetanide injections (1184, 1185) or forcing early overexpression of KCC2 (which extrudes Cl−) (161).”
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Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on SubtypeIn medial entorhinal cortex, CCKBCs innervate PCs that project to the contralateral cortex but avoid neighboring PCs that project to the hippocampal dentate gyrus.
“In medial entorhinal cortex, CCKBCs innervate PCs that project to the contralateral cortex but avoid neighboring PCs that project to the hippocampal dentate gyrus (1162) (FIGURE 8D).”
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Premisecitation§ C. The Preoptic AreaOtx2 promotes PVBC maturation as well as further PNN development.
“PNNs also facilitate the capture and uptake of the transcription factor Otx2, which in turn promotes PVBC maturation as well as further PNN development (100, 173, 912, 1063).”
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Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on SubtypeIn the neocortex, PVBCs are more likely to innervate and evoke larger amplitude IPSCs in neighboring PCs that provide reciprocal excitation.
“For example, in the neocortex, PVBCs are more likely to innervate and evoke larger amplitude IPSCs in neighboring PCs that provide reciprocal excitation (1252).”
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Premisecitation§ C. The Preoptic AreaPNNs are structures of the extracellular matrix that form around PVBCs and stabilize synapses.
“Interestingly, closure of the critical period coincides with the establishment of perineuronal nets (PNNs), which are structures of the extracellular matrix that form around PVBCs and stabilize synapses (for reviews, see Refs. 1039, 1183).”
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Premisecitation§ C. The Preoptic AreaDegrading PNNs or blocking their formation reopens or extends the critical period into adulthood.
“Importantly, degrading PNNs or blocking their formation reopens or extends the critical period into adulthood (173, 912).”
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Premisecitation§ C. The Preoptic AreaRendering GABA hyperpolarizing during the first postnatal week by block of NKCC1 leads to reduced BDNF release and results in late closure of the critical period.
“Rendering GABA hyperpolarizing during the first postnatal week by block of NKCC1 leads to reduced BDNF release and results in late closure of the critical period (265).”
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Interpretationreasoning§ C. The Preoptic AreaInhibition is necessary to open critical periods, but once it reaches a threshold level of maturity, the potential for plasticity is diminished and the critical period ends.
“Thus inhibition is necessary to open critical periods, but once it reaches a threshold level of maturity, the potential for plasticity is diminished and the critical period ends.”
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Premisecitation§ C. The Preoptic AreaBlocking the ability of Otx2 to bind to PNNs results in their degradation and reopens the critical period in adults.
“Similarly, blocking the ability of Otx2 to bind to PNNs results in their degradation and reopens the critical period in adults (100).”
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Premisecitation§ C. The Preoptic AreaSensitivity to MD can be reestablished in adult mice by suppressing GABA synthesis or reducing PVBC firing rates.
“However, this potential remains in mature circuits, as sensitivity to MD can be reestablished in adult mice by suppressing GABA synthesis or reducing PVBC firing rates (465, 614).”
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Interpretationreasoning§ I. PCs and Interneurons Form Selective Microcircuits Dependent on SubtypeWhile many interneuron subtypes are promiscuous in their targeting of PCs, it is likely that subtype specific microcircuits exist to carry out different cortical and hippocampal computations.
“Thus, while many interneuron subtypes are certainly promiscuous in their targeting of PCs, it is likely that subtype specific microcircuits exist to carry out different cortical and hippocampal computations.”
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Premisecitation§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONSMost studies agreed that interneuron resting membrane potentials were more depolarized and that many cells demonstrated rapid and nonaccommodating firing patterns in response to electrotonic depolarizing current steps.
“Indeed, most studies agreed that interneuron resting membrane potentials were more depolarized and that many cells demonstrated rapid and nonaccommodating firing patterns in response to electrotonic depolarizing current steps (1130, 1131).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesTheir rapid activation ensures efficient spike repolarization, and their rapid deactivation allows minimal K+ current accumulation during the interspike interval that would interfere with generation of subsequent action potentials.
“Their rapid activation ensures efficient spike repolarization, and their rapid deactivation allows minimal K+ current accumulation during the interspike interval that would interfere with generation of subsequent action potentials.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesOutside-out nucleated patch recordings from identified CA1 SST-positive O-LM cells revealed that three voltage-gated K+ current types predominate in this cell type: a fast delayed rectifier, a slow delayed rectifier, and a rapidly inactivating A-type current.
“Outside-out nucleated patch recordings from identified CA1 SST-positive O-LM cells revealed that three voltage-gated K+ current types predominate in this cell type (TABLE 2) (678).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThe kinetic properties of these conductances were typically rapid and possessed pharmacologies that diverged from those observed in pyramidal cells.
“The kinetic properties of these conductances were typically rapid and possessed pharmacologies that diverged from those observed in pyramidal cells.”
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Premisecitation§ I. PCs and Interneurons Form Selective Microcircuits Dependent on SubtypeIn CA1 of the hippocampus, PVBCs are more likely to be innervated by and receive the largest excitatory drive from prefrontal cortex projecting PCs.
“Finally, in CA1 of the hippocampus, PVBCs evoke larger IPSCs in PCs that project to the amygdala than those that project to the prefrontal cortex; conversely, PVBCs are more likely to be innervated by and receive the largest excitatory drive from prefrontal cortex projecting PCs (656) (FIGURE 8E).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesA second slower delayed rectifier component with intermediate sensitivity to TEA and a rapid inactivating A-type current component blocked by 4-AP but resistant to TEA were also identified in PVBCs.
“A second slower delayed rectifier (20–80% rise time ~6 ms) component with intermediate sensitivity to TEA and a rapid inactivating A-type current component blocked by 4-AP but resistant to TEA were also identified (756).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThe kinetic properties of this current in PVBCs are remarkably rapid with the 20-80% rise time being <1 ms and showing little, if any, inactivation during a 100-ms voltage step.
“The kinetic properties of this current are remarkably rapid with the 20–80% rise time being <1 ms and showing little, if any, inactivation during a 100-ms voltage step.”
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Study design and conductnone given§ IV. PHYSIOLOGICAL PROPERTIES OF INHIBITORY INTERNEURONSSmall changes in slice preparations, intracellular solution composition, and recording quality and resolution often alter ion reversal potentials, channel availability, and open probability, making measurement of a true resting potential or other intrinsic conductances problematic.
“Small changes in slice preparations, intracellular solution composition, and recording quality and resolution (e.g., access resistance, junction potentials) often alter ion reversal potentials, channel availability, and open probability, making measurement of a “true” resting potential (Vm) or other intrinsic conductances problematic.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThe activation and inactivation curves are less steep in O-LM cells compared with PVBCs, and the deactivation of the predominantly Kv3.2 channels in the O-LM cells is slower than the equivalent Kv3.1 containing channels in PVBCs.
“Although many of the kinetic properties were similar, the activation and inactivation curves are less steep in O-LM cells compared with PVBCs, and the deactivation of the predominantly Kv3.2 channels in the O-LM cells is slower than the equivalent Kv3.1 containing channels in PVBCs.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBoth Kv1.1 and Kv1.2 are expressed in axons of PV-containing interneurons.
“In addition to the Kv3 subunits, both Kv1.1 and Kv1.2 are expressed in axons of PV-containing interneurons.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesImmunohistochemistry reveals Kv3.2 expression is primarily across the somatodendritic arbor of virtually all PV-containing cells, ~85% of nNOS-positive cells, and ~50% of SST-containing interneurons.
“Immunohistochemistry reveals Kv3.2 expression is primarily across the somatodendritic arbor of virtually all PV-containing cells, ~85% of nNOS-positive cells, and ~50% of SST-containing interneurons.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBoth Kv1.1 and Kv1.2 are highly enriched at the axon initial segment where they colocalize with the voltage-gated sodium channel Nav1.6.
“Both Kv1.1 and Kv1.2 are highly enriched at the axon initial segment where they colocalize with the voltage-gated sodium channel Nav1.6 (415, 695).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThe rapid activation kinetics of Kv3 channels enforces a narrow temporal window that minimizes Na+ channel inactivation, and the consequent deep hyperpolarization serves to deinactivate other voltage-gated channels ensuring a high fraction are available for activation during trains of action potentials.
“Importantly, the rapid activation kinetics enforces a narrow temporal window that minimizes Na+ channel inactivation, and the consequent deep hyperpolarization serves to deinactivate other voltage-gated channels ensuring a high fraction are available for activation during trains of action potentials (967).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesRowan et al. recently demonstrated that Kv3 channels are clustered at individual presynaptic boutons and are usually spared from axonal shafts.
“Rowan et al. (957) recently demonstrated that Kv3 channels are clustered at individual presynaptic boutons and are usually spared from axonal shafts.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesPKA phosphorylation of Kv3.2 channels in both PVBCs and SST-containing interneurons broadens the action potential waveform and reduces the maximal firing frequency in both cell types, consequently modulating network oscillatory activity.
“PKA phosphorylation of Kv3.2 channels in both PVBCs and SST-containing interneurons broadens the action potential waveform and reduces the maximal firing frequency in both cell types consequently modulating network oscillatory activity (49).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesKv3.1b is largely expressed across the soma, dendrites, as well as the axons of PV-containing interneurons and is completely absent in SST-containing or any other interneuron type.
“Kv3.1b is largely expressed across the soma, dendrites, as well as the axons of PV-containing interneurons and is completely absent in SST-containing or any other interneuron type (287).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBlockade of Kv1.1 eliminates the delay to first spike typically observed in these cells and converts the cell to a continuous high-frequency firing mode.
“In support of this, blockade of Kv1.1 eliminates the delay to first spike typically observed in these cells and converts the cell to a continuous high-frequency firing mode.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThese axonal Kv3 channels control local spike repolarization and act as key determinants of the compartmentalized control of action potential width in a synapse by synapse manner.
“These axonal Kv3 channels control local spike repolarization and act as key determinants of the compartmentalized control of action potential width in a synapse by synapse manner (957).”
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Premisecitation§ C. Voltage-Gated K+ ConductancescAMP and PKA phosphorylation inhibits current through Kv3.2 channels but not Kv3.1b.
“cAMP and PKA phosphorylation inhibits current through Kv3.2 channels but not Kv3.1b.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesKv4.3 subunits are highly enriched in neocortical and hippocampal interneurons and are thought to underlie the 4-AP-sensitive, A-type inactivating K+ conductance in these cells.
“Kv4.3 subunits are highly enriched in neocortical and hippocampal interneurons (678, 756, 782, 944, 999) and are thought to underlie the 4-AP-sensitive, A-type inactivating K+ conductance in these cells.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesHu et al. reasoned that Kv1 channels may impose a fast coincidence detection mechanism in PV-containing interneurons, allowing fast EPSPs to beat Kv1 activation leading to a rapid action potential initiation with little delay.
“In consideration of these data, Hu et al. (502) reasoned that Kv1 channels may impose a fast coincidence detection mechanism in PV-containing interneurons, allowing fast EPSPs to beat Kv1 activation leading to a rapid action potential initiation with little delay.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesDendritic Kv3 currents act to accelerate the decay time course of excitatory postsynaptic potentials (EPSPs), imposing a narrow window for temporal integration, and minimize the impact of clustered excitatory input to favor distributed synaptic inputs.
“Dendritic Kv3 currents act to accelerate the decay time course of excitatory postsynaptic potentials (EPSPs), imposing a narrow window for temporal integration (504, 967), and minimize the impact of clustered excitatory input to favor distributed synaptic inputs (504).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBoth Kv1.1 and Kv1.2 have low voltage activation thresholds and slower activation when compared with the Kv3 family and underlie the conductance known as the D-type K+ current.
“Both Kv1.1 and Kv1.2 have low voltage activation thresholds and slower activation when compared with the Kv3 family and underlie the conductance known as the D-type K+ current (245, 415).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThis intrinsic plasticity results in increased excitability and recruitment of PV-containing cells, which arises through an mGluR5-dependent downregulation of currents through Kv1 channels.
“This intrinsic plasticity results in increased excitability and recruitment of PV-containing cells, which arises through an mGluR5-dependent downregulation of currents through Kv1 channels.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesAt early postnatal stages, action potential firing is slow and unable to sustain periods of high-frequency activity.
“At early postnatal stages, action potential firing is slow and unable to sustain periods of high-frequency activity.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn mouse models of Dravet syndrome cortical interneurons cannot sustain high-frequency firing, leading to circuit disinhibition, seizures, and premature death.
“In mouse models of Dravets syndrome cortical interneurons cannot sustain high-frequency firing, leading to circuit disinhibition, seizures, and premature death (194, 852).”
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Interpretationcitation§ C. Voltage-Gated K+ ConductancesSignificant A-type current can be active at potentials close to rest and have roles in physiological processes other than action potential repolarization.
“Using a small interfering RNA knock down approach, Bourdeau et al. (119) implicated Kv4.3 containing channels in the generation of these subthreshold membrane potential oscillations, suggesting that significant A-type current can be active at potentials close to rest and have roles in physiological processes other than action potential repolarization.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesKChIP1 is found exclusively in hippocampal interneurons where it overlaps with Kv4.3.
“The potassium channel interacting proteins (KChIPs) are Ca2+-binding proteins, which interact with the cytoplasmic NH2-terminal domain of Kv4 channels and KChIP1 is found exclusively in hippocampal interneurons where it overlaps with Kv4.3 (782, 944).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesA dominant loss of function mutation in Nav1.1 causes Dravet syndrome, an intractable form of childhood-onset epilepsy that arises from a reduction in Na+ channel density in hippocampal interneurons.
“Finally, a dominant loss of function mutation in Nav1.1 causes Dravet syndrome, an intractable form of childhood-onset epilepsy that arises from a reduction in Na+ channel density in hippocampal interneurons (1255).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesKChIPs are Ca2+-binding proteins, which interact with the cytoplasmic NH2-terminal domain of Kv4 channels.
“The potassium channel interacting proteins (KChIPs) are Ca2+-binding proteins, which interact with the cytoplasmic NH2-terminal domain of Kv4 channels and KChIP1 is found exclusively in hippocampal interneurons where it overlaps with Kv4.3 (782, 944).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesOf the total Kv4.3/KChIP1 coexpression, 26% was contributed by PV-containing neurons, ~18% by SST-containing, ~20% by CB-containing, and ~34% by CR-containing interneurons.
“Of the total Kv4.3/KChIP1 coexpression, 26% was contributed by PV-containing neurons, ~18% by SST-containing, ~20% by CB-containing, and ~34% by CR-containing interneurons (782).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesReduced Nav1.1 levels and PV-containing interneuron dysfunction critically contribute to abnormalities in oscillations, synchrony, and memory in human amyloid precursor protein transgenic mice and possibly in humans with Alzheimer's disease.
“Reduced Nav1.1 levels and PV-containing interneuron dysfunction critically contribute to abnormalities in oscillations, synchrony, and memory in human amyloid precursor protein transgenic mice and possibly in humans with Alzheimers disease (1170).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesAlthough the voltage dependence of activation was similar between the two cell types, the deactivation kinetics differed, being more rapid in basket cells (~0.13 vs. 0.2 ms at −40 mV).
“Although the voltage dependence of activation was similar between the two cell types, the deactivation kinetics differed, being more rapid in basket cells (~0.13 vs. 0.2 ms at −40 mV).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesNative Kv4 containing channels typically associate with auxiliary subunits, which act to modify their expression levels and biophysical properties.
“Native Kv4 containing channels typically associate with auxiliary subunits, which act to modify their expression levels and biophysical properties (530).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesThe peak Na+ conductance density in O-LM cell dendrites was measured at ~110 pS/μm2 at −10 mV, about three times that seen on cortical pyramidal cell dendrites.
“The peak Na+ conductance density in O-LM cell dendrites was measured at ~110 pS/μm2 at −10 mV (757), about three times that seen on cortical pyramidal cell dendrites (1059, but cf. with PV-containing axons described above).”
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Premisenone given§ C. Voltage-Gated K+ ConductancesCav2.1 channels are particularly enriched in axon terminals of PV-containing interneurons, whereas Cav2.2 are preferentially expressed in CCK-containing cell axons.
“Cav2.1 channels (P/Q type) are particularly enriched in the axon terminals of PV-containing interneurons, whereas Cav2.2 (N-type channels) are preferentially expressed in CCK-containing cell axons (see sect. IVL for their roles in neurotransmitter release mechanisms).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesHigh-frequency synaptic activity of mGluR5 induces selective and compartmentalized potentiation of L-type channels by a PKC-dependent mechanism and release of Ca2+ from ryanodine-sensitive intracellular stores.
“high-frequency synaptic activity of mGluR5 induces a selective and compartmentalized potentiation of L-type channels by a PKC-dependent mechanism and release of Ca2+ from ryanodine-sensitive intracellular stores (1111).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn cortex and hippocampus, general expression of T-type channel subunits Cav3.1 and Cav3.2 increases during development to peak at P21.
“In cortex and hippocampus, general expression of T-type channel subunits Cav3.1 and Cav3.2 increases during development to peak at P21 (10).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn recordings from about 150 CA1 interneurons, virtually all cells displayed a voltage-dependent sag during current pulses, and this sag was largest in SST- and CCK-containing interneurons.
“Tricoire et al. (1138) noted that in recordings from ~150 CA1 interneurons that while virtually all cells displayed a voltage-dependent sag during current pulses, this sag was largest in the SST- and CCK-containing interneurons (FIGURE 9 and TABLE 1).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBoth Cav1.2 and Cav1.3 are largely expressed on the cell bodies and dendrites of PV-containing interneurons and are absent from the axonal compartment.
“Both Cav1.2 and Cav1.3 are largely expressed on the cell bodies and dendrites of PV-containing interneurons and are absent from the axonal compartment (533).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn principal neurons, Ih channel density increases as a function of distance from the soma.
“In principal neurons, Ih channel density increases as a function of distance from the soma (730).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIh in O-LM interneurons is blocked by external Cs+ and ZD7288 and potentiated by norepinephrine and isoprenaline.
“Ih is blocked by both external Cs+ and ZD7288 (FIGURE 11, A and B) and potentiated by the monoamine adrenergic agonists norepinephrine and isoprenaline (718).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesA multicompartment modeling study suggests Ih is dendritically expressed in O-LM cells.
“Although it is unclear whether the Ih density is similarly distributed in interneuron dendrites, a multicomparment modeling study suggests that Ih is dendritically expressed in O-LM cells (994).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesTetrodotoxin-insensitive depolarizations and action potentials are common in young (PN5-7) PV-containing cells but largely absent by PN25, consistent with loss of functional T-type channels.
“Although tetrodotoxin-insensitive depolarizations and action potentials are common in young (PN5–7) PV-containing cells, they are largely absent by PN25 consistent with the loss of functional T-type channels in these cells (857).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesCav3.1 expression in G42-positive cortical fast spiking basket cells is downregulated during the first few weeks of postnatal life, likely contributing to a decrease in cell excitability upon maturation.
“In contrast, Cav3.1 expression in G42-positive cortical fast spiking basket cells is downregulated during the first few weeks of postnatal life, likely contributing to a decrease in cell excitability upon maturation (857).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIh in O-LM interneurons is activated at potentials close to −50 mV, with a mid activation point of approximately −80 mV, and makes a major contribution to the total membrane conductance at rest.
“Ih in these cells is activated at potentials close to −50 mV, with a mid activation point of approximately −80 mV and makes a major contribution to the total membrane conductance at rest.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn PVBCs and cortical irregular-spiking supragranular interneurons, the voltage-gated transient potassium current IA restricts action potential propagation and limits dendritic Ca2+ channel activation.
“This is in marked contrast to Ca2+ dynamics in PVBCs and cortical “irregular-spiking” supragranular interneurons where the voltage-gated transient potassium current IA restricts action potential propagation and limits dendritic Ca2+ channel activation (417, 418).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesActivation of T-type channels on PV-containing axons by nicotinic acetylcholine receptors can trigger asynchronous transmitter release, which can be augmented by concomitant Ca2+ release from presynaptic intracellular stores.
“Activation of T-type channels on PV-containing axons by nicotinic acetylcholine receptors can trigger asynchronous transmitter release, which can be augmented by a concomitant Ca2+ release from presynaptic intracellular stores (1093).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIh in O-LM interneurons is inhibited by activation of mu and delta opioid receptors as well as nicotinic receptors.
“Ih in O-LM interneurons is inhibited by activation of mu and delta opioid receptors (1071) as well as nicotinic receptors (435).”
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Premisereasoning§ C. Voltage-Gated K+ ConductancesBlock of Ih results in membrane hyperpolarization accompanied by increased cell input resistance.
“Since Ih is active at potentials close to rest, its blockade results in membrane hyperpolarization accompanied by increased cell input resistance.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIM in O-LM cells is active at resting potentials close to −50 mV and is blocked by linopirdine, TEA, and XE-991 and enhanced by the Kv7 channel opener retigabine.
“IM in O-LM cells is active at resting potentials close to −50 mV and is blocked by the antagonists linopirdine, TEA, and XE-991 and enhanced by the Kv7 channel opener retigabine (645) (FIGURE 11C).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesSST-containing O-LM cells typically express transcripts for both ASIC1a and ASIC2 channels, whereas only ASIC1a is expressed in DG PVBCs.
“SST-containing O-LM cells typically express transcripts for both ASIC1a and ASIC2 channels, whereas only ASIC1a is expressed in DG PVBCs (1196).”
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Interpretationcitation§ C. Voltage-Gated K+ ConductancesInterneuron presynaptic ASICs are not the molecular substrate responsible for terminating electrographic seizures.
“suggesting that interneuron presynaptic ASICs are not the molecular substrate responsible for terminating electrographic seizures.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesDisruption of the Asic1a gene or pharmacological block of ASIC1 increased seizure severity.
“Indeed, Zeimann et al. (1277) demonstrated that disruption of the Asic1a gene or pharmacological block of ASIC1 increased seizure severity.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesAcidification of the extracellular fluid to levels achieved during electrographic events triggers activation of ASIC1a channels on interneurons, increases interneuron cell firing, and promotes increased inhibitory tone onto principal cells.
“Acidification of the extracellular fluid to levels achieved during electrographic events triggers activation of ASIC1a channels on interneurons, increases interneuron cell firing, and promotes increased inhibitory tone onto principal cells (1277).”
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- The authors state this as an assumption: Extracellular acidification during seizures activates ASIC channels on both principal and inhibitory interneurons.
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Premisecitation§ C. Voltage-Gated K+ ConductancesASIC currents in O-LM cells possess markedly rapid recoveries from desensitization (0.96 s) compared with PVBC currents (42.8 s), suggesting that the latter may accumulate in a desensitized state more readily.
“ASIC currents in O-LM cells possess markedly rapid recoveries from desensitization (0.96 s) compared with PVBC currents (42.8 s), suggesting that the latter may accumulate in a desensitized state more readily (1196).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBlock of presynaptic ASIC channels by compound 5 triggers an increase in the frequency of spontaneous IPSCs onto principal cells, suggesting that presynaptically active ASICs on as yet unidentified interneurons normally act to dampen spontaneous inhibitory tone in the hippocampal circuit.
“Block of presynaptic ASIC channels by an orthosteric noncompetitive antagonist 2-oxo-2H-chromene-3-carboxamidine (aka compound 5), triggers an increase in the frequency of spontaneous IPSCs onto principal cells, suggesting that presynaptically active ASICs on as yet unidentified interneurons normally act to dampen spontaneous inhibitory tone in the hippocampal circuit (516).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn DG PVBCs, Ih channels depolarize the axon and reduce the threshold for action potential initiation, thereby increasing spike reliability.
“In DG PVBCs, Ih channels depolarize the axon and reduce the threshold for action potential initiation thereby increasing spike reliability (43).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn DG PV-containing fast spiking basket cells, the biophysical properties of Ih were somewhat similar to those described in O-LM cells and had a role in establishing resting potential, input resistance, and the membrane time constant.
“In a study of PV-containing fast spiking basket cells in the DG, Aponte et al. (43) observed that the biophysical properties of Ih were somewhat similar to those described in O-LM cells and had a role to play in establishing resting potential, input resistance, and the membrane time constant.”
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Premisecitation§ C. Voltage-Gated K+ ConductancesEmergence of the ADP results from an inhibition of IM and the slow AHP, concomitant with activation of a nonselective cation conductance.
“Emergence of the ADP results from an inhibition of IM and the slow AHP, concomitant with activation of a nonselective cation conductance (182, 640, 645).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIn hippocampus, ASICs are expressed in both principal cells and inhibitory interneurons, and the latter have the larger current density.
“In hippocampus, although ASICs are expressed in both principal cells and inhibitory interneurons, the latter have the larger current density (113, 205, 1196, 1277).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesBlockade of Ih by ZD7288 reduces the frequency, but not the amplitude, of mIPSCs, suggesting that Ih channels are located close to individual transmitter release sites and can influence transmitter release probability.
“Moreover, blockade of Ih by ZD7288 reduces the frequency, but not the amplitude, of mIPSCs, suggesting that Ih channels are located close to individual transmitter release sites and can influence transmitter release probability (Pr).”
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Premisecitation§ I. TASK ChannelsHigher levels of TASK3 and lower levels of TASK1 are typically expressed in hippocampal interneurons.
“Although both channel types are widely expressed in principal cells, higher levels of TASK3 and lower levels of TASK1 are typically expressed in hippocampal interneurons (1083, 1099).”
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Premisecitation§ C. Voltage-Gated K+ ConductancesIM is best studied in CA1 SST-containing O-LM cells, which express Kv7.2 and Kv7.3 protein on their soma and dendrites, suggesting that native IM arises from their heteromeric assembly.
“IM has been best studied in CA1 SST-containing O-LM cells, which express Kv7.2 and Kv7.3 protein on their soma and dendrites, suggesting that native IM arises from their heteromeric assembly (645, 646) (FIGURE 11C).”
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Premisecitation§ I. TASK ChannelsMiyoshi et al. observed that a divergent population of CGE-derived cells parsed into nine distinct subtypes based on morphology, cell layer positioning, firing patterns, and other intrinsic properties.
“They observed that this divergent population of CGE-derived cells parsed into nine distinct subtypes based on morphology, cell layer positioning, firing patterns, and other intrinsic properties.”
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Premisecitation§ I. TASK ChannelsMost (97%) PV-containing interneurons, as well as a subpopulation of SST-containing interneurons including O-LM cells, are heavily decorated by TASK3 immunoreactivity.
“Of these, most (97%) PV-containing interneurons, as well as a subpopulation of SST-containing interneurons including O-LM cells, are heavily decorated by TASK3 immunoreactivity (1099, 1113).”
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Premisecitation§ I. TASK ChannelsCells in clusters 4 and 5 had similar electrophysiological properties with high input resistances (430 and 401 MΩ, respectively) and slow membrane time constants (57 and 5 ms, respectively).
“Cells in clusters 4 and 5 had similar electrophysiological properties with high input resistances (430 and 401 MΩ, respectively) and slow membrane time constants (57 and 5 ms, respectively).”
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Premisenone given§ 1. PV-containing interneuronsAction potential initiation site in PV cells is extremely close to the soma (within 20 μm), and spike initiation is reliable and seldom fails.
“The action potential initiation site is extremely close to the soma (within 2 0μm), and spike initiation of the AP is reliable and seldom fails.”
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Premisecitation§ I. TASK ChannelsClusters 1 and 2 comprised solely MGE-derived inhibitory neurons, whereas clusters 4, 5, and 6 comprised only cells of CGE origin.
“Clusters 1 and 2 were comprised solely of MGE-derived inhibitory neurons, whereas clusters 4, 5, and 6 comprised only cells of CGE origin (FIGURE 12).”
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Premisecitation§ I. TASK ChannelsUnsupervised cluster analyses (Wards and K-means) including 20 features of intrinsic excitability and firing properties were performed on identified MGE- and CGE-derived hippocampal interneurons.
“Unsupervised cluster analyses (Wards and K-means) that included 20 features of intrinsic excitability and firing properties were performed (FIGURES 9 and 12 and TABLE 1).”
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Premisecitation§ 1. PV-containing interneuronsAxons of PVBCs typically innervate the soma and proximal dendrites of principal cells, while those of AACs form chandelier-like strings that selectively innervate the axon initial segments of principal cell targets.
“The axons of PVBCs typically innervate the soma and proximal dendrites of principal cells, while those of AACs form “chandelier”-like strings that selectively innervate the axon initial segments of principal cell targets (352) (FIGURE 2, A–D).”
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Interpretationcitation§ 1. PV-containing interneuronsThe biophysical properties of these Na+ channels (primarily Nav1.1 and Nav1.6), coupled with axonal expression of Kv3-containing voltage-gated K+ channels, ensure brief-duration action potentials that depolarize and repolarize rapidly and ensure rapid and efficient channel deinactivation such that a large fraction of channels are available for subsequent action potential initiation.
“The biophysical properties of these Na+ channels (primarily Nav1.1 and Nav1.6), coupled with the axonal expression of Kv3-containing voltage-gated K+ channels, ensures brief-duration action potentials that depolarize and repolarize rapidly, and importantly ensure rapid and efficient channel deinactivation such that a large fraction of channels are available for subsequent action potential initi”
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Interpretationreasoning§ 1. PV-containing interneuronsThese biophysical properties allow firing at high frequencies and rapid propagation through an increasingly small axonal compartment to ensure high fidelity of transmission to downstream targets.
“These biophysical properties allow firing at high frequencies and rapid propagation through an increasingly small axonal compartment to ensure high fidelity of transmission to downstream targets (65, 503, 755).”
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Premisecitation§ I. TASK ChannelsThe second population of NPY-expressing cells are SST-containing Martinotti-like cells with axons that ascend into layer 1 and represent the most excitable cell type.
“2) The second population are SST-containing Martinotti-like cells with axons that ascend into layer 1 and represent the most excitable cell type.”
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Premisecitation§ 1. PV-containing interneuronsAction potentials in PV cells are brief (~0.5 ms), and propagation speeds are extraordinarily fast with orthodromic speeds of ~0.25-1.5 ms−1 reported using direct axonal recordings.
“Action potentials are brief (~0.5 ms) (TABLE 1), and propagation speeds are extraordinarily fast with orthodromic speeds of ~0.25–1.5ms-1 being reported using direct axonal recordings (277, 503).”
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Premiseown data§ I. TASK ChannelsCluster 1 comprised cells expressing PV- and SST-mRNA transcripts and possessed the fastest membrane time constants (13 ms) and steady-state firing frequencies (mean 70 Hz).
“Cluster 1 comprised cells expressing PV- and SST-mRNA transcripts and possessed the fastest membrane time constants (13 ms) and steady-state firing frequencies (mean 70 Hz) (TABLE 1).”
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Premisecitation§ I. TASK ChannelsActivation of 5HT2A receptors of entorhinal cortex interneurons increases their excitability by a mechanism involving inhibition of TASK3 channels.
“Moreover, activation of 5HT2A receptors of entorhinal cortex interneurons increases their excitability by a mechanism involving inhibition of TASK3 channels (269).”
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Premiseown data§ 1. PV-containing interneuronsAxons of single PV interneurons extensively arborize to form en passant boutons (~10,000 in the CA1 hippocampus), which provide synchronous robust inhibitory control of their downstream targets.
“The axons of single PV interneurons extensively arborize to form en passant boutons (~10,000 in the CA1 hippocampus), which provide synchronous robust inhibitory control of their downstream targets (FIGURES 2C, 9A, and 13).”
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Premisecitation§ I. TASK ChannelsCells in cluster 6 had the highest incidence of CCK expression (typically in combination with VGluT3 and VIP) and anatomies indicative of CCKBCs and mossy fiber associated cells, with intrinsic features often intermediate to cells in all other clusters.
“Finally, cells in cluster 6 had the highest incidence of CCK expression (typically in combination with VGluT3 and VIP) and anatomies indicative of CCKBCs (1031, 584) and mossy fiber associated cells (1138) with intrinsic features that were often intermediate to cells in all other clusters (TABLE 1).”
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Premisecitation§ I. TASK ChannelsCells in cluster 2 possessed slower membrane time constants (46 ms) and firing frequencies (~20 Hz), typically exhibited significant voltage-dependent sag indicative of Ih, and expressed SST-mRNA transcripts.
“Cells in cluster 2 possessed slower membrane time constants (46 ms) and firing frequencies (~20 Hz), typically exhibited significant voltage-dependent sag indicative of Ih, and expressed SST-mRNA transcripts.”
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Interpretationcitation§ 2. CCK-containing cellsAsynchronous release appears to be a general property of CCK-containing interneurons and correlates with the class of presynaptic CCK interneuron but is largely independent of postsynaptic target identity.
“Asynchronous release appears to be a general property of CCK-containing interneurons and correlates with the class of presynaptic CCK interneuron but is largely independent of postsynaptic target identity (258, 554).”
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Interpretationreasoning§ 2. CCK-containing cellsAn asynchronous mode of transmitter release will endow CCK cells with prolonged inhibitory control over their postsynaptic targets, a mechanism distinct from the temporal precision enforced by PVBCs.
“Functionally one can imagine that an asynchronous mode of transmitter release will endow CCK cells with prolonged inhibitory control over their postsynaptic targets, a mechanism distinct from the temporal precision enforced by PVBCs.”
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Premisecitation§ 1. PV-containing interneuronsSignal duration from DG PVBC axons increases with distance to principal cell targets, likely due to changes in postsynaptic GABAA receptor subunit composition.
“Inhibitory strength declined (presumably due to lower contact numbers) and signal duration was increased with distance (likely due to changes in postsynaptic GABAA receptor subunit composition) between the presynaptic cell and the downstream targets.”
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Interpretationcitation§ 2. CCK-containing cellsThis form of inhibition from CCK cells is prolonged and temporally imprecise.
“Indeed, in paired recordings, one striking feature of asynchronous release is the long temporal window of transmitter release that continues many 100s of milliseconds after termination of presynaptic firing (258, 477), underscoring that this form of inhibition is prolonged and temporally imprecise (FIGURE 13B).”
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Premisecitation§ 2. CCK-containing cellsElimination of dominant presynaptic Ca2+ sensor synaptotagmin isoforms (Syt2 at the Calyx of Held or Syt1 at DG cell synapses) selectively eliminates synchronous release, revealing an increase in asynchronous release.
“Elimination of dominant presynaptic Ca2+ sensor synaptotagmin isoforms (Syt2 at the Calyx of Held or Syt1 at DG cell synapses) (576, 1066) selectively eliminates synchronous release revealing an increase in asynchronous release, suggesting that separate Ca2+ sensors may underlie the two modes of release.”
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Premisecitation§ 2. CCK-containing cellsAction potential conduction velocities of CCK cells are thought to be slower than those of PVBCs, since evoked unitary IPSCs occur with longer delays than at PVBC synapses.
“Although studies similar to those described above for PV-containing cells have not been made for CCK cells (or for any other interneuron subtype for that matter), their action potential conduction velocities are thought to be slower than those of PVBCs since evoked unitary IPSCs occur with longer delays than that seen at PVBC synapses (FIGURE 13, A and B) (477).”
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Interpretationreasoning§ 1. PV-containing interneuronsPV cells play a role in enforcing temporally precise feedforward/feedback-inhibitory control and in generating coherent oscillations within cortical ensembles.
“Thus, through a combination of anatomical and molecular specializations, action potential initiation, propagation, and presynaptic invasion are “tuned” to ensure rapid and reliable neurotransmission to downstream targets, consistent with a role for these cells in enforcing temporally precise feedforward/feedback-inhibitory control as well as the generation of coherent oscillations within cortical”
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Interpretationcitation§ 1. PV-containing interneuronsThe small number of Ca2+ channels at each release site coupled to syt2-mediated neurotransmitter release favors fast temporally precise synchronous phasic transmitter release, making PVBCs rapid signaling devices capable of providing precisely timed inhibition onto postsynaptic cells.
“As a consequence of these molecular specializations, the small number of Ca2+ channels at each release site coupled to syt2-mediated neurotransmitter release favors fast temporally precise “synchronous” phasic transmitter release, thus making them rapid signaling devices capable of providing precisely timed inhibition onto their postsynaptic cells (64, 502) (FIGURE 13).”
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Premisecitation§ 3. NGFCsElectrical synapses are essentially bidirectional and rapidly transmit voltage changes at speeds slightly faster than chemical synapses.
“Of particular importance electrical synapses are essentially bidirectional and rapidly transmit voltage changes at speeds slightly faster than chemical synapses (970).”
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Premisecitation§ 3. NGFCsIn contrast to the rapid and synchronous IPSCs produced by PVBCs, transmission from NGFCs generates long-lasting IPSCs resulting from prolonged GABA transients that arise from the unusual synaptic architecture where bouton density is high but close apposition to specialized postsynaptic densities is low.
“Of particular interest, in contrast to the rapid and synchronous IPSCs produced by PVBCs, transmission from NGFCs generates long-lasting IPSCs resulting from prolonged GABA transients (550, 1074, 1086) that arise from the unusual synaptic architecture where bouton density is high but close apposition to specialized postsynaptic densities is low (550, 751, 858, 1074) (FIGURE 13C).”
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Interpretationcitation§ 3. NGFCsThe cloud of GABA released from NGFCs is strongly influenced by GABA uptake mechanisms and acts on GABAA and GABAB receptors located on any nearby neuronal element, including the releasing cell itself, potentially producing suppression of neural activity in a widespread area dictated by their dense NGFC axonal arbor.
“Moreover, the cloud of GABA released from NGFCs is strongly influenced by GABA uptake mechanisms (FIGURE 13D) and acts on GABAA and GABAB receptors located on any nearby neuronal element, including the releasing cell itself, potentially producing suppression of neural activity in a widespread area dictated by their dense NGFC axonal arbor (870).”
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Interpretationreasoning§ 3. NGFCsThe low pass nature of the coupling severely truncates rapid events such as action potentials and favors slower depolarizations/hyperpolarizations such as AHPs.
“The low pass nature of the coupling severely truncates rapid events such as action potentials and favors slower depolarizations/ hyperpolarizations such as AHPs.”
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Premisecitation§ 3. NGFCsThe vast majority of NGFC presynaptic boutons are spatially located at a larger than usual distance from their target dendrites and are often not in register with any clear postsynaptic structure.
“One feature of NGFC axons separating them from all other inhibitory interneurons is that the vast majority of presynaptic boutons are spatially located at a larger than usual distance from their target dendrites and are often not in register with any clear postsynaptic structure (858, 870).”
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Premisecitation§ 3. NGFCsNGFCs of layer 2/3 (but not layer 1) of rat somatosensory cortex are highly interconnected via electrical synapses and also make widespread electrical synapses with PVBCs, regular spiking nonpyramidal cells, AACs as well as many other unidentified interneuron cell types.
“One interesting deviation from this canonical rule are NGFCs of layer 2/3 (but not layer 1) (206) of rat somatosensory cortex. Although these cells were highly interconnected via electrical synapses, they also made widespread electrical synapses with PVBCs, regular spiking nonpyramidal cells, AACs as well as many other unidentified interneuron cell types (1017).”
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Premisenone given§ 3. NGFCsSST-containing cells make few GABAergic synapses onto each other but are highly connected via electrical synapses.
“In contrast, SST-containing cells make few GABAergic synapses onto each other but are highly connected via electrical synapses.”
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Premisecitation§ 3. NGFCsIn IvC, NGFCs, and PVBCs of several cortical and hippocampal regions, persistent firing is generated within the distal axon compartment, requires Ca2+ elevation and gap junction coupling, and persists for several minutes on cessation of the trigger.
“In IvC, NGFCs [called perforant path associated HTr5b-GFP cells of SR/SLM border in (1000)], and PVBCs of several cortical and hippocampal regions persistent firing is generated within the distal axon compartment, requires Ca2+ elevation and gap junction coupling, and persists for several minutes on cessation of the trigger.”
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Interpretationcitation§ 3. NGFCsSuch coupling is rapid and bidirectional facilitating coordinated inhibitory synaptic transmission onto downstream principal cells, as well as triggering synchronous oscillatory activity across neural networks.
“Such coupling is rapid and bidirectional facilitating coordinated inhibitory synaptic transmission onto downstream principal cells, as well as triggering synchronous oscillatory activity across neural networks (80, 375, 1128).”
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Interpretationcitation§ 3. NGFCsEvents such as the action potential AHP, which are faithfully transmitted across electrical synapses, serve to deinactivate intrinsic voltage-gated conductances across the many connected cells, allowing for simultaneous cell activation once the AHP relaxes, further enhancing synchronous activity.
“Events such as the action potential AHP, which are faithfully transmitted across electrical synapses, serve to deinactivate intrinsic voltage-gated conductances across the many connected cells. This allows for simultaneous cell activation once the AHP relaxes, further enhancing synchronous activity (107, 397, 671).”
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Interpretationcitation§ 3. NGFCsThe low and prolonged GABA transient favors postsynaptic receptor desensitization and results in use-dependent synaptic depression as receptors accumulate in desensitized states.
“This low and prolonged GABA transient favors postsynaptic receptor desensitization and results in use-dependent synaptic depression as receptors accumulate in desensitized states (550).”
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Premisecitation§ 3. NGFCsAction potentials when propagated across gap junctions are severely truncated and manifest themselves as "spikelets" of a few millivolts that are capable of triggering rapid depolarizations that can facilitate activation of voltage-dependent conductances and trigger coordinated spiking across clusters of coupled interneurons.
“Action potentials when propagated across gap junctions are severely truncated and manifest themselves as “spikelets” of a few millivolts that are capable of triggering rapid depolarizations that can facilitate activation of voltage-dependent conductances and trigger coordinated spiking across clusters of coupled interneurons.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ V. GLUTAMATE RECEPTORSInhibitory interneurons are embedded within complex neuronal networks of interconnected principal glutamatergic cells and GABAergic interneurons and thus participate in almost all forms of network activity.
“Inhibitory interneurons are embedded within complex neuronal networks of interconnected principal glutamatergic cells and GABAergic interneurons and thus participate in almost all forms of network activity.”
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Premisecitation§ V. GLUTAMATE RECEPTORSGluA1 or GluA4 loss-of-function experiments show compromised gamma oscillations and impairments in hippocampal-dependent working memory.
“GluA1 or GluA4 loss-of-function experiments show compromised gamma oscillations and impairments in hippocampal-dependent working memory (364).”
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Premisenone given§ V. GLUTAMATE RECEPTORSThe principal form of excitation onto interneurons arises via activation of ionotropic and metabotropic glutamate receptors by glutamate, the primary neurotransmitter within the central nervous system.
“The principal form of excitation onto interneurons arises via activation of ionotropic and metabotropic glutamate receptors by glutamate, the primary neurotransmitter within the central nervous system.”
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Premisecitation§ V. GLUTAMATE RECEPTORSThe M2 reentrant transmembrane loop of the AMPAR subunit forms the lining of the channel pore, and amino acids in the "QRN" site determine the ion selectivity of the channel.
“The M2 reentrant transmembrane loop of the AMPAR subunit forms the lining of the channel pore, and amino acids in the so-called “QRN” site determine the ion selectivity of the channel (1133).”
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Premisecitation§ 3. NGFCsInduction of persistent firing is inhibited (at least in hippocampal NPY-expressing Ivy cells) by activation of μ-opioid peptide receptors, which act to either hyperpolarize the NGFC or inhibit the locally connected gap-junction-network between cells.
“Induction is inhibited (at least in hippocampal NPY-expressing Ivy cells) by activation of μ-opioid peptide receptors (606), which act to either hyperpolarize the NGFC or inhibit the locally connected gap-junction-network between cells.”
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Premisecitation§ V. GLUTAMATE RECEPTORSMossy fiber axons of DG granule cells innervated GluA2-lacking CP-AMPAR dominated synapses, whereas inputs from associational fibers of CA3 pyramidal cells onto the same cell innervated GluA2-containing, CI-AMPAR dominated synapses.
“Mossy fiber axons of DG granule cells innervated GluA2-lacking CP-AMPAR dominated synapses, whereas inputs from associational fibers of CA3 pyramidal cells onto the same cell innervated GluA2-containing, CI-AMPAR dominated synapses.”
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Premisecitation§ V. GLUTAMATE RECEPTORSThese origin specific AMPAR profiles are consistent across a broad developmental age range and importantly demonstrate that, at least at SC synapses onto CA1 subfield inhibitory interneurons, GluA2 expression is not developmentally regulated as seen at some principal cell synapses.
“These origin specific AMPAR profiles are consistent across a broad developmental age range and importantly demonstrate that, at least at SC synapses onto CA1 subfield inhibitory interneurons, GluA2 expression is not developmentally regulated as seen at some principal cell synapses (492).”
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Premisecitation§ V. GLUTAMATE RECEPTORSThroughout the central nervous system, the vast majority of fast synaptic neurotransmission arises via AMPARs.
“Throughout the central nervous system, the vast majority of fast synaptic neurotransmission arises via AMPARs (1133).”
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Premisecitation§ 3. NGFCsPersistent firing occurs in NGFCs both in vitro and in vivo, although in vivo it occurs less frequently and requires more prolonged barrages of action potential activity for initiation in neocortical NGFCs.
“Importantly, persistent firing, which likely provides a global “brake” on local excitability, occurs in NGFCs both in vitro and in vivo, although in vivo it occurs less frequently and requires more prolonged barrages of action potential activity for initiation in neocortical NGFCs (1069).”
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Premisecitation§ V. GLUTAMATE RECEPTORSThese GluA1/4 containing AMPARs generate synaptic currents that possess unusually rapid kinetics, have high Ca2+ permeability, and show strong inward rectification due to block by intracellular polyamines.
“These GluA1/4 containing AMPARs generate synaptic currents that possess unusually rapid kinetics, have high Ca2+ permeability, and show strong inward rectification due to block by intracellular polyamines (644).”
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Premisecitation§ V. GLUTAMATE RECEPTORSUnlike mature hippocampal and cortical principal cells, which do not typically express GluA4, PV-containing interneurons possess a high level of GluA4 and a lower level of GluA2 subunit expression.
“Unlike mature hippocampal and cortical principal cells, which do not typically express GluA4, PV-containing interneurons possess a high level of GluA4 and a lower level of GluA2 subunit expression (388, 630, 886, 1242).”
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Premisecitation§ V. GLUTAMATE RECEPTORSImmature synapses onto PV-containing interneurons lack GluA4 and are comprised of GluA1 homomers.
“However, immature synapses onto PV-containing interneurons lack GluA4 and are comprised of GluA1 homomers (886).”
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Premisecitation§ V. GLUTAMATE RECEPTORSSchaffer collateral synapses onto MGE-derived interneurons (e.g., PV-, SST-, and nNOS-containing interneurons) typically express CP-AMPARs, whereas CGE-derived interneurons (CR, VIP, CCK, reelin, and some nNOS interneurons) mostly express CI-AMPARs.
“Schaffer collateral synapses onto MGE-derived interneurons (e.g., PV-, SST-, and nNOS-containing interneurons) typically express CP-AMPARs, whereas CGE-derived interneurons (CR, VIP, CCK, reelin, and some nNOS interneurons) mostly express CI-AMPARs.”
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Premisecitation§ V. GLUTAMATE RECEPTORSUnlike GluA1, GluA3 and GluA4 subunits which contain an unedited glutamine (Q), most GluA2 subunits contain a fully edited arginine (R) at this site, which has important consequences for single channel conductance, Ca2+-permeability, and channel block by polyamines.
“Unlike GluA1, GluA3 and GluA4 subunits which contain an unedited glutamine (Q) most GluA2 subunits contain a fully edited arginine (R) at this site which has important consequences for single channel conductance, Ca2+-permeability, and channel block by polyamines (1133).”
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Premisecitation§ V. GLUTAMATE RECEPTORSOverexpression of the GluA2 subunit slows the AMPAR kinetics and disrupts long range synchrony, underscoring the importance of synaptic AMPARs with rapid kinetics in these cells.
“Similarly, overexpression of the GluA2 subunit slows the AMPAR kinetics and disrupts long range synchrony underscoring the importance of synaptic AMPARs with rapid kinetics in these cells (365).”
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Premisenone given§ 3. NGFCsAlthough axonal action potential firing is required to trigger persistent firing, somatic depolarization is not.
“Although axonal action potential firing is required to trigger persistent firing, somatic depolarization is not.”
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Premisecitation§ V. GLUTAMATE RECEPTORSThe mechanisms whereby single interneurons can manufacture these distinct AMPARs and target them to specific dendritic domains remain poorly understood, but such selective targeting has been observed at numerous cells throughout the mammalian central nervous system.
“The mechanisms whereby single interneurons can manufacture these distinct AMPARs and target them to specific dendritic domains remain poorly understood, but such selective targeting has been observed at numerous cells throughout the mammalian central nervous system (for review, see Ref. 1120).”
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Premisereasoning§ 3. NGFCsIn paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell, suggesting that activity can percolate through the network via electrical coupling.
“In paired recordings, persistent firing was not restricted to the stimulated neuron; it could also be produced in the unstimulated cell, suggesting that activity can percolate through the network via electrical coupling.”
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Premisecitation§ V. GLUTAMATE RECEPTORSGluA4 was significantly higher and GluA2 significantly lower at PV cell synapses than observed at principal cell synapses.
“However, GluA4 was significantly higher and GluA2 significantly lower at PV cell synapses than observed at principal cell synapses.”
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Premisecitation§ V. GLUTAMATE RECEPTORSNative AMPARs are typically homomeric or heteromeric assemblies of the four subunits, GluA1-4.
“Native AMPARs are typically homomeric or heteromeric assemblies of the four subunits, GluA1–4 (572, 822, 955).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsSelective ablation of NMDARs later in development in PV-positive interneurons alters theta and gamma oscillations and impairs spatial and short- and long-term memory.
“Selective ablation of NMDARs later in development in PV-positive interneurons alters theta and gamma oscillations with consequent impairments in spatial and short- and long-term memory tests, indicating a critical role for NMDARs in PV-interneuron-mediated circuit entrainment (82, 599).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsTonic extrasynaptic NMDAR-mediated currents have been identified on PV-containing interneurons of the prefrontal cortex and CA1 s.r., suggesting a novel role for extrasynaptic NMDARs on interneurons in addition to synaptic transmission.
“Indeed, tonic extrasynaptic NMDAR-mediated currents have been identified on PV-containing interneurons of the prefrontal cortex (925) and CA1 s.r. (946), suggesting a novel role for extrasynaptic NMDARs on interneurons in addition to their role in synaptic transmission.”
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Interpretationcitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsIt is hard to reconcile the hypothesis that PV interneuron synaptic NMDAR hypofunction is an underpinning for schizophrenia, suggesting alternative roles for NMDARs other than conventional synaptic transmission must exist in these cells early in development.
“it is hard to reconcile the hypothesis that PV interneuron synaptic NMDAR hypofunction is an underpinning for schizophrenia (825), suggesting that alternative roles for NMDARs other than conventional synaptic transmission must exist in these cells early in development.”
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Premisecitation§ V. GLUTAMATE RECEPTORSMost if not all AMPAR subunits exist in a complex with a number of channel auxiliary subunits that bind to a variety of targets on the pore forming subunit to modify receptor expression and recycling, as well as their biophysical and plastic properties.
“Most if not all AMPAR subunits exist in a complex with a number of channel auxiliary subunits that bind to a variety of targets on the pore forming subunit to modify receptor expression and recycling, as well as their biophysical and plastic properties (1243).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsAt mossy fiber synapses onto CI-AMPAR interneuron synapses with high NMDA/AMPAR ratios, a train of stimuli triggers multiple action potentials at each stimulus followed by a large late NMDAR-dependent depolarizing envelope that persists long after the stimulus.
“Similarly at mossy fiber synapses onto CI-AMPAR interneuron synapses, which exhibit high NMDA/AMPAR ratios, a train of stimuli triggers multiple action potentials at each stimulus followed by a large late NMDAR-dependent depolarizing envelope that persists long after the stimulus.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsNPTX2 is an immediate early gene highly enriched at excitatory synapses onto PV-containing interneurons and promotes activity dependent accumulation of GluA4-containing AMPARs.
“NPTX2 is an immediate early gene highly enriched at excitatory synapses onto PV-containing interneurons and promotes activity dependent accumulation of GluA4-containing AMPARs (189).”
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Interpretationreasoning§ V. GLUTAMATE RECEPTORSWhether this MGE- versus CGE-origin specific AMPAR expression exists at other synapses remains to be demonstrated, but suggests that embryonic origin provides a strong predictor of glutamate receptor expression.
“Whether this MGE- versus CGE-origin specific AMPAR expression exists at other synapses remains to be demonstrated, but suggests that embryonic origin provides a strong predictor of glutamate receptor expression.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsElimination of GluN1 from CGE-derived CA1 s.l.m. NGFCs arrests maturation of both pre- and postsynaptic elements, resulting in higher frequency and amplitude of EPSCs and exuberant cell morphology.
“In contrast, elimination of GluN1 from CGE-derived CA1 s.l.m. NGFCs arrests maturation of both pre- and postsynaptic elements such that a higher frequency and amplitude of EPSCs is observed, coupled to an exuberance of cell morphology (Chittajallu and McBain, unpublished observation).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsThe neuronal pentraxin family (NPTX1, NPTX2, and NPTXR) is a family of Ca2+-dependent lectins that are highly enriched at excitatory synapses throughout the adult brain.
“The neuronal pentraxin family (NPTX1, NPTX2, and NPTXR) is a family of Ca2+-dependent lectins that are highly enriched at excitatory synapses throughout the adult brain (1140).”
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Premisecitation§ V. GLUTAMATE RECEPTORSIn γ2 knockout mice, AMPAR density was markedly reduced at excitatory synapses onto PV-containing interneurons but surprisingly was unaffected at synapses onto the cell cohort labeled as "non-PV," suggesting a TARP functional redundancy at the latter synapses.
“In γ2 knockout mice, AMPAR density was markedly reduced at excitatory synapses onto PV-containing interneurons but surprisingly was unaffected at synapses onto the cell cohort labeled as “non-PV,” suggesting a TARP functional redundancy at the latter synapses.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsAll three NPTXs form disulfide-linked assemblies that bind to the NH2-terminal domain of AMPARs and promote receptor clustering.
“All three NPTXs form disulfide-linked assemblies that bind to the NH2-terminal domain of AMPARs and promote receptor clustering (1008, 1229).”
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Premisecitation§ V. GLUTAMATE RECEPTORSThe TARP family comprises six isoforms, which differentially modify almost every function of native AMPARs.
“The TARP family comprises six isoforms, which differentially modify almost every function of native AMPARs (1133).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsThis decreased excitatory drive promotes hippocampal seizures and subsequent lethality.
“This decreased excitatory drive promotes hippocampal seizures and subsequent lethality (574).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsKR activation by exogenous kainate robustly increases interneuron excitability, triggers action potential firing, and boosts spontaneous inhibitory drive onto pyramidal cells.
“KR activation by exogenous kainate robustly increases interneuron excitability, triggers action potential firing, and boosts spontaneous inhibitory drive onto pyramidal cells (230, 348).”
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Premisenone given§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsNPTX1 and NPTX2 (or Narp) are secreted proteins, whereas NPTXR possesses a transmembrane domain and can function to anchor NPTX complexes to plasma membranes.
“Of these, NPTX1 and NPTX2 (or Narp) are secreted proteins, whereas NPTXR possesses a transmembrane domain and can function to anchor NPTX complexes to plasma membranes.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsSimilar genetic manipulation results in increased cell death of adult born olfactory bulb granule cells, indicating NMDARs play different roles in cell survival across different brain regions or developmental stages.
“In contrast, similar genetic manipulation resulted in increased cell death of adult born olfactory bulb granule cells (573), indicating that NMDARs play different roles in cell survival across different brain regions or developmental stages.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsKR-mediated inward currents in CA3 s.r. interneurons are absent in GluK2 loss-of-function mice but not GluK1 knockouts, consistent with a role for GluK2 containing KRs on specific CA3 interneuron populations.
“In contrast, KR-mediated inward currents in CA3 s.r. interneurons are absent in GluK2 loss-of-function mice but not GluK1 knockouts, consistent with a role for GluK2 containing KRs on specific CA3 interneuron populations (332).”
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Premisenone given§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsStudies of NPTX2 in regulating excitatory drive onto PV-containing cells revealed only a homeostatic role for NPTX2 and required mice to be pretreated with stimuli that induce NPTX2 expression.
“However, studies of NPTX2 in regulating excitatory drive onto PV-containing cells revealed only a homeostatic role for NPTX2 and required mice to be pretreated with stimuli that induce NPTX2 expression.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsElimination of GluN1 in CA1 s.l.m. NGFCs results in cells with more complex dendritic arbors, with dendrites shifting from a stellate form to one polarized towards termination zones of afferents from entorhinal cortex and thalamic nucleus reuniens.
“In contrast, elimination of GluN1 in CA1 s.l.m. NGFCs results in cells with more complex dendritic arbors, with dendrites shifting from a stellate form to one polarized towards the termination zones of afferents from the entorhinal cortex and thalamic nucleus reuniens (Chittajallu and McBain, unpublished observation).”
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Premisecitation§ V. GLUTAMATE RECEPTORSMost AMPARs complex with transmembrane AMPA regulatory proteins (TARPs).
“Of these accessory proteins, most AMPARs complex with transmembrane AMPA regulatory proteins (TARPs) (1107).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsCortical interneurons originate in the ventral telencephalon and migrate tangentially into the neocortex and hippocampus.
“As described in section III, cortical interneurons originate in the ventral telencephalon and migrate tangentially into the neocortex and hippocampus (747).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsThese KR-mediated synaptic events comprise a significant fraction (~30%) of the total spontaneous EPSC population.
“These studies were the first to suggest that KR synaptic events may exist in isolation from synapses containing AMPARs, and importantly these events comprise a significant fraction of the total spontaneous EPSC population (~30%).”
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Premisereasoning§ 2. Group II and III mGluRsmGluR-mediated depression of inhibitory transmission is accompanied by a reduction in presynaptic Pr, thus enhancing paired pulse facilitation at these synapses.
“mGluR-mediated depression of inhibitory transmission is accompanied by a reduction in presynaptic Pr, thus enhancing paired pulse facilitation at these synapses.”
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Premisecitation§ I. Delta Glutamate ReceptorsAlthough GluD2 is not thought to act as an ion channel, it does interact with mGluR1, which can trigger currents through GluD2.
“Although GluD2 is not thought to act as an ion channel, it does interact with the metabotropic glutamate receptor mGluR1, which can trigger currents through GluD2 (9).”
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Premisecitation§ 1. Group I mGluRsActivation of mGluRs directly depolarizes interneurons and alters the frequency of sIPSCs and sEPSCs onto cells, suggesting complex pre- and postsynaptic roles for mGluRs in regulating interneuron excitability.
“Before the advent of reasonably selective ligands, activation of mGluRs was observed to directly depolarize interneurons and alter the frequency of sIPSCs and sEPSCs onto cells, suggesting complex pre- and postsynaptic roles for mGluRs in regulating interneuron excitability (270, 393, 768, 789, 869, 917).”
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Premisecitation§ I. Delta Glutamate ReceptorsGluD2 is expressed predominantly in cerebellar Purkinje cells and plays an important role in long-term depression at parallel fiber-Purkinje cell synapses.
“The GluD2 subunit is expressed predominantly in cerebellar Purkinje cells and plays an important role in long-term depression at parallel fiber-Purkinje cell synapses (595), and acts as a synaptic organizer via interactions with both pre- and postsynaptic elements (546).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsPresynaptic GluK1-containing KRs on CCK/CB1R-containing interneurons are regulated by both Neto1 and Neto2, with Neto1 being required for presynaptic KR function and Neto2 modulating KR affinity.
“Presynaptic GluK1-containing KRs on CCK/CB1R-containing interneurons are regulated by both Neto1 and Neto2, with Neto1 being required for presynaptic KR function and Neto2 modulating KR affinity (Wyeth, Pelkey, and McBain, unpublished observation).”
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Premisecitation§ I. Delta Glutamate ReceptorsHepp et al. showed wide expression of both GluD1 and GluD2 throughout the hippocampal formation.
“Hepp et al. (484) showed wide expression of both GluD1 and GluD2 throughout the hippocampal formation.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsOren et al. found no evidence for spontaneous KR-mediated events in recordings from the same cell population and concluded that the vast majority of spontaneous EPSCs in s.o. O-LM cells were AMPAR mediated.
“However, Oren et al. (867) found no evidence for spontaneous KR-mediated events in recordings from the same cell population and concluded that the vast majority of spontaneous EPSCs in s.o. O-LM cells were AMPAR mediated (1215).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsIn paired electrophysiological recordings, GluK1 containing KR activation decreases presynaptic release from CCK-containing but not PV-containing interneurons at release sites onto pyramidal but not interneuron targets.
“In paired electrophysiological recordings, GluK1 containing KR activation decreases presynaptic release from CCK-containing but not PV-containing interneurons that is observed at release sites onto pyramidal but not interneuron targets (256).”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsGoldin et al. suggested that KRs, but not AMPARs, on SST-positive O-LM cells entrain spiking at theta frequencies, suggesting an important role in oscillatory activity.
“Goldin et al. (420) suggested that KRs, but not AMPARs, on SST-positive O-LM cells entrain spiking at theta frequencies, suggesting an important role in oscillatory activity.”
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Premisecitation§ 1. Group I mGluRsThe mGluR1α isoform is particularly enriched in CA1 SST-containing interneurons, but the overlap between mGluR1α and SST is incomplete.
“Somogyi and colleagues subsequently demonstrated that the mGluR1α isoform is particularly enriched in CA1 SST-containing interneurons (75, 326); however, the overlap between mGluR1α and SST is incomplete.”
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Premisecitation§ C. AMPAR Auxiliary/Interacting Proteins; Neuronal PentraxinsNeto1, but not Neto2, regulates postsynaptic KR currents in all three interneuron subtypes as well as the KR-mediated recruitment of inhibitory drive onto pyramidal cells.
“Neto1, but not Neto2, regulates postsynaptic KR currents in all three interneuron subtypes as well as the KR-mediated recruitment of inhibitory drive onto pyramidal cells.”
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Premisecitation§ 1. Group I mGluRsBoth mGluR1α and mGluR5 are expressed on both DG and CA1/CA3 PVBCs.
“however, a recent study using both immunohistochemistry and quantitative immunoelectron microscopy has shown both mGluR1α and mGluR5 to be expressed on both DG and CA1/CA3 PVBCs (447).”
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Premisereasoning§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSSynaptic facilitation increases recruitment of NMDARs by removing the voltage-dependent Mg2+ block, expanding the temporal window of excitation and recruiting an essential route for Ca2+ entry.
“Furthermore, synaptic facilitation will act to increase the recruitment of NMDARs by removing the voltage-dependent Mg2+ block, expanding the temporal window of excitation as well as recruiting an essential route for Ca2+ entry.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSAn NMDAR-independent form of LTP was identified in SST-containing interneurons of the s.o. (primarily O-LM cells) and subsequently observed in PVBCs, and AACs.
“The first, an NMDAR-independent form of LTP was identified in SST-containing interneurons of the s.o. (primarily O-LM cells) and subsequently observed in PVBCs, and AACs (867, 896).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSLoss of Elfn1 normalizes transmission across the train of stimuli, with only weak facilitation remaining, suggesting that other factors must be involved in establishing the high Pr of pyramidal neuron-basket cell synapses.
“Rather, loss of Elfn1 normalizes transmission across the train of stimuli, with only weak facilitation remaining (1073), suggesting that other factors must be involved in establishing the high Pr of pyramidal neuron-basket cell synapses.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSThe same presynaptically expressed LTP can be triggered at these synapses by theta-burst stimulation and postsynaptic depolarization and requires activation of group I mGluRs.
“The same presynaptically expressed LTP can be triggered at these synapses by theta-burst stimulation and postsynaptic depolarization and requires activation of group I mGluRs (896).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSSynapses with a low initial Pr show facilitation upon repetitive activation, whereas those with high Prs typically demonstrate short-term depression.
“In general, synapses with a low initial Pr show facilitation upon repetitive activation, whereas those with high Prs typically demonstrate short-term depression (938).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSLoss of Elfn1 reduces the amount of presynaptic mGluR7 which leads to an increased Pr.
“Indeed, loss of Elfn1 reduces the amount of presynaptic mGluR7 which leads to an increased Pr (172).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSElfn1 expression increases during postnatal development and is instructive in recruiting presynaptic mGluR7-containing glutamatergic processes onto SST-containing interneurons.
“Elfn1 expression increases during postnatal development and is instructive in recruiting presynaptic mGluR7-containing glutamatergic processes onto SST-containing interneurons (1106).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSIn the CA1 hippocampus, CP-AMPARs are primarily expressed at synapses onto interneurons derived from the MGE (PV-, SST-, and nNOS/NPY-containing interneurons) and largely absent from CGE-derived cells.
“In the CA1 hippocampus, CP-AMPARs are primarily expressed at synapses onto interneurons derived from the MGE (PV-, SST-, and nNOS/NPY-containing interneurons) and largely absent from CGE-derived cells (763), suggesting that this novel form of plasticity is intimately linked to the circuit functions provided by MGE-derived interneurons.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSThis induction paradigm triggers mGluR1 and mGluR5 activation and also requires postsynaptic Ca2+ elevation together with Src/ERK and TRP channel activation.
“This induction paradigm triggers mGluR1 and mGluR5 activation and also requires postsynaptic Ca2+ elevation together with Src/ERK and TRP channel activation (634, 896, 1110).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSThis LTP predominates at synapses comprising CP-AMPARs and has been termed "anti-Hebbian".
“This LTP predominates at synapses comprising CP-AMPARs and has been termed “anti-Hebbian” (633).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSRelief of polyamine block is both use and voltage dependent, providing these synapses with a novel form of postsynaptic short-term plasticity.
“The relief of polyamine block is both use and voltage dependent, providing these synapses with a novel form of postsynaptic short-term plasticity (959, 1121).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSInterneurons lack Ca2+/calmodulin-dependent kinase IIa, which is an essential component of the NMDAR-dependent cascade that underlies LTP at glutamatergic synapses onto principal cells, suggesting that alternative mechanisms must exist for LTP/LTD onto interneurons.
“Although NMDAR-dependent plasticity has been observed at synapses onto interneurons (see below for further discussion), interneurons lack Ca2+/calmodulin-dependent kinase IIa (686, 1012), which is an essential component of the NMDAR-dependent cascade that underlies LTP at glutamatergic synapses onto principal cells (682), suggesting that alternative mechanisms must exist for LTP/LTD onto interneur”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSHigh-frequency afferent stimulation or a 5-Hz stimulation coupled with postsynaptic hyperpolarization triggers an LTP that requires a postsynaptic Ca2+ elevation, but appears to have a presynaptic expression locus coupled to increased Pr.
“High-frequency afferent stimulation or a 5-Hz stimulation coupled with postsynaptic hyperpolarization triggers an LTP that requires a postsynaptic Ca2+ elevation, but appears to have a presynaptic expression locus coupled to increased Pr (867).”
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Premisenone given§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSIn the CA1 hippocampus, transmission between CA1 pyramidal cells and PV-containing interneurons shows marked short-term depression during repetitive activation, while the same presynaptic input to SST-containing interneurons shows facilitation.
“In the CA1 hippocampus, transmission between CA1 pyramidal cells and PV-containing interneurons shows marked short-term depression during repetitive activation, while the same presynaptic input to SST-containing interneurons shows facilitation.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSViral vector-mediated Elfn1 knock down or knockout of Elfn1 reduces the magnitude of short-term facilitation, confirming a role for Elfn1 in establishing a low Pr.
“Viral vector-mediated Elfn1 knock down (1073), or knockout of Elfn1 (1106) reduces the magnitude of short-term facilitation, confirming a role for Elfn1 in establishing a low Pr.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSThe vast majority of plastic changes at synapses onto principal cells rely on activation of the NMDAR, which acts as a coincidence detector, and the primary route of Ca2+ entry that triggers downstream second messenger cascades to ultimately influence AMPAR trafficking.
“Although a number of potentially distinct, but overlapping mechanisms have been identified at synapses onto principal cells, the vast majority of these plastic changes rely on activation of the NMDAR, which acts as a coincidence detector, and the primary route of Ca2+ entry that triggers downstream second messenger cascades to ultimately influence AMPAR trafficking (509).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSAxons of cerebellar stellate cell interneurons possess variable action potential widths at presynaptic bouton sites within the same axon branch.
“A recent study by Rowan et al. (957) demonstrated that axons of cerebellar stellate cell (SC) interneurons possess variable action potential widths at presynaptic bouton sites within the same axon branch.”
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Premisenone given§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSShort-term facilitation of glutamatergic synaptic responses transiently brings the postsynaptic membrane voltage closer to threshold for action potential firing.
“At the simplest level, short-term facilitation of glutamatergic synaptic responses transiently brings the postsynaptic membrane voltage closer to threshold for action potential firing.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSCP-AMPARs are both Ca2+ permeable and blocked in a voltage-dependent manner by cytoplasmic polyamines, such as spermine and spermidine.
“As described in section VA, CP-AMPARs are both Ca2+ permeable and blocked in a voltage-dependent manner by cytoplasmic polyamines, such as spermine and spermidine (1133).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSLocalized expression of Kv3-containing voltage-gated potassium channels at individual boutons dictates site-specific spike repolarization at each release site.
“Localized expression of Kv3-containing voltage-gated potassium channels at individual boutons dictate site-specific spike repolarization at each release site.”
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Premisecitation§ 2. Group II and III mGluRsInhibitory transmission from s.o. interneurons (which use P/Q Ca2+ channels for transmission) is insensitive to DCG-IV, indicating a lack of group II mGluRs on this cell type.
“In contrast, inhibitory transmission from s.o. interneurons (which use P/Q Ca2+ channels for transmission) was insensitive to DCG-IV, indicating a lack of group II mGluRs on this cell type.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSRepetitive activation of most central synapses results in a short-term increase (facilitation) or decrease (depression) of subsequent postsynaptic events.
“Repetitive activation of most central synapses results in a short-term increase (facilitation) or decrease (depression) of subsequent postsynaptic events (938).”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSSo far, NMDAR-independent LTP has largely been observed at synapses between CA1 pyramidal cells and their downstream interneuron targets and does not typically occur at Schaffer collateral synapses onto interneurons residing in the s.r.
“So far, NMDAR-independent LTP has largely been observed at synapses between CA1 pyramidal cells and their downstream interneuron targets and does not typically occur at Schaffer collateral synapses onto interneurons residing in the s.r. (867).”
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Premisenone given§ 4. Mossy fiber-dentate gyrus basket cell synapsesPresynaptically expressed NMDAR-independent anti-Hebbian LTP requires either mGluR or mACh receptor activation and occurs primarily at synapses comprised of CP-AMPARs.
“In addition, presynaptically expressed NMDAR-independent “anti-Hebbian” LTP requires either mGluR or mACh receptor activation and occurs primarily at synapses comprised of CP-AMPARs.”
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Premisenone given§ 4. Mossy fiber-dentate gyrus basket cell synapsesIn the DG, PVBCs receive feedforward excitation via entorhinal cortex perforant pathway inputs and feedback excitation from mossy fiber afferents.
“In the DG, PVBCs receive feedforward excitation via entorhinal cortex perforant pathway inputs and feedback excitation from mossy fiber afferents.”
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Premisenone given§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapsesMossy fiber LTP onto the same cells also requires PKC formation, but this LTP is independent of CaMKII activation instead of relying upon a cAMP PKA signaling cascade.
“While mossy fiber LTP onto the same cells also requires PKC formation, this LTP is independent of CaMKII activation instead of relying upon a cAMP PKA signaling cascade.”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesRepeated coactivation of the two inputs triggers associative LTP at mossy fiber synapses, which requires Ca2+ entry via CP-AMPARs.
“Repeated coactivation of the two inputs triggers associative LTP at mossy fiber synapses, which requires Ca2+ entry via CP-AMPARs (972).”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesmGluR7b is highly enriched at mossy fiber synapses onto s.l. interneurons but not CA3 pyramidal cells, and functions as a metaplastic switch controlling bidirectional plasticity.
“mGluR7b, which is highly enriched at mossy fiber synapses onto s.l. interneurons (but not CA3 pyramidal cells), functions as a metaplastic switch controlling bidirectional plasticity.”
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Premisecitation§ VI. SYNAPTIC PLASTICITY OF GLUTAMATERGIC TRANSMISSION ONTO INTERNEURONSAn NMDA-dependent form of LTP exists at synapses onto some s.o. interneurons, low-threshold spiking interneurons of the somatosensory cortex, and at Schaffer collateral synapses onto a subset of aspiny interneurons residing in the CA1 s.r.
“An NMDA-dependent form of LTP exists at synapses onto some s.o. interneurons (869), low-threshold spiking interneurons of the somatosensory cortex (705), and at Schaffer collateral synapses onto a subset of aspiny interneurons residing in the CA1 s.r. (631).”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesHigh-frequency stimulation of mossy fibers triggers presynaptic LTP at synapses onto CA3 pyramidal cells but triggers LTD at naive synapses onto s.l. interneurons.
“High-frequency stimulation of mossy fibers triggers a presynaptic form of LTP at synapses onto CA3 pyramidal cells but triggers LTD at naive synapses onto s.l. interneurons (722, 889).”
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Premisecitation§ C. CA1 Hippocampal Interneuron LTD12-(S)-HPETE functions as a retrograde signaling messenger, and its liberation from the postsynaptic compartment allows it to diffuse to the presynaptic site and activate the nonselective cation channel TRPV1.
“12-(S)-HPETE functions as a retrograde signaling messenger, and its liberation from the postsynaptic compartment allows it to diffuse to the presynaptic site and activate the nonselective cation channel TRPV1 (395).”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesMossy fiber boutons onto downstream principal cell targets, primarily CA3 pyramidal cells, are extremely large (~10 μm in diameter) and possess numerous well-defined presynaptic release sites with low Pr, engulfing their postsynaptic dendritic targets to form the thorny excrescence synapse.
“Mossy fiber boutons onto downstream principal cell targets (primarily CA3 pyramidal cells) are extremely large (~10 μm in diameter) and possess numerous well-defined presynaptic release sites with low Pr, which engulf their postsynaptic dendritic targets to form the so-called thorny excrescence synapse (7, 201).”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesThese filopodial extensions are small in diameter and possess only a single high Pr release site.
“These filopodial extensions are small in diameter and possess only a single high Pr release site (641, 662).”
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Premisenone given§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapsesNMDAR-dependent plasticity at s.r. inputs on CI-AMPAR synapses requires postsynaptic Ca2+ elevation and activation of Ca2+/calmodulin-dependent protein kinase II and PKC.
“NMDAR-dependent plasticity at s.r. inputs on CI-AMPAR synapses requires postsynaptic Ca2+ elevation and activation of Ca2+/calmodulin-dependent protein kinase II and PKC.”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesMGE-derived CA1 interneurons exclusively express CP-AMPARs at Schaffer collateral synapses, and this subset comprises PV-, SOM-, and NPY-containing interneurons, all of which express anti-Hebbian NMDAR-independent LTP.
“Matta et al. (763) observed that MGE-derived CA1 interneurons exclusively express CP-AMPARs at Schaffer collateral synapses, and this subset comprises PV-, SOM-, and NPY-containing interneurons, all of which express “anti-Hebbian” NMDAR-independent LTP.”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesAs a consequence of binding glutamate, mGluR7b is rapidly internalized, and subsequent rounds of the induction protocol now induce a presynaptic form of LTP via a cAMP-dependent mechanism identical to that observed at mossy fiber principal cell synapses.
“As a consequence of binding glutamate, mGluR7b is rapidly internalized, and subsequent rounds of the induction protocol now induce a presynaptic form of LTP via a cAMP-dependent mechanism identical to that observed at mossy fiber principal cell synapses (891).”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesKullmann and Lamsa recognized that the cells in which NMDAR-dependent LTP was most readily observed tended to possess the largest NMDAR-mediated conductances.
“Kullmann and Lamsa (619) recognized that the cells in which NMDAR-dependent LTP was most readily observed tended to possess the largest NMDAR-mediated conductances.”
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Premisecitation§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapsesWhen postsynaptic mGluR1s are blocked, the same induction paradigm now triggers LTD, which requires Ca2+ entry through L-type Ca2+ channels.
“When postsynaptic mGluR1s are blocked, the same induction paradigm now triggers LTD, which requires Ca2+ entry through L-type Ca2+ channels (377, 378).”
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Premisereasoning§ C. CA1 Hippocampal Interneuron LTDThis LTD and sensitivity to 12-(S)-HPETE are absent in TRPV1 loss-of-function mice, confirming a role for TRPV1 channels in interneuron LTD.
“This LTD and sensitivity to 12-(S)-HPETE are absent in TRPV1 loss-of-function mice, confirming a role for TRPV1 channels in interneuron LTD.”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesLTP induction at these synapses requires a postsynaptic elevation in Ca2+ and PKC activation but is expressed presynaptically.
“LTP induction requires a postsynaptic elevation in Ca2+ and PKC activation but is expressed presynaptically.”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesGlutamate liberated by the induction paradigm triggers activation of presynaptic mGluR7b, which reduces presynaptic Ca2+ entry through P/Q Ca2+ channels by a mechanism involving PKC, resulting in LTD.
“Glutamate liberated by the induction paradigm triggers activation of presynaptic mGluR7b, which reduces presynaptic Ca2+ entry through P/Q Ca2+ channels by a mechanism involving PKC (887, 890; for reviews, see Ref. 772), resulting in LTD.”
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Premisecitation§ 2. Mossy fiber-stratum lucidum interneuron synapsesAt CI-AMPARs, this LTD is NMDAR dependent and possesses a postsynaptic locus of induction and expression that relies on NSF/AP2-dependent AMPAR internalization.
“At CI-AMPARs, this LTD is NMDAR dependent and possesses a postsynaptic locus of induction and expression that relies on NSF/AP2-dependent AMPAR internalization (662).”
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Premisecitation§ 3. Mossy fiber-stratum lacunosum moleculare interneuron synapsesStimulation of afferents onto CI-AMPAR synapses triggers an LTD that relies on postsynaptic mGluR1 activation and requires an IP3-mediated elevation of intracellular Ca2+, or entry through L-type Ca2+ channels and PKA and PKC activation.
“Stimulation of afferents onto CI-AMPAR synapses triggers an LTD, which relies on postsynaptic mGluR1 activation and requires an IP3-mediated elevation of intracellular Ca2+, or entry through L-type Ca2+ channels and PKA and PKC activation.”
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Premisereasoning§ 4. Mossy fiber-dentate gyrus basket cell synapsesAlthough LTP and LTD exist at glutamatergic synapses onto interneurons, they are not universally observed in all interneuron types.
“It is worthwhile pointing out that although LTP and LTD undoubtedly exist at glutamatergic synapses onto interneurons, they are not universally observed in all interneuron types.”
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Premisecitation§ 1. CA3 pyramidal–s.r. interneuron synapsesInduction of this plasticity requires Ca2+ entry through postsynaptic CP-AMPARs and activation of presynaptic mGluR7.
“Induction of this plasticity requires Ca2+ entry through postsynaptic CP-AMPARs and activation of presynaptic mGluR7 (for review, see Ref. 625).”
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Interpretationreasoning§ 1. CA3 pyramidal–s.r. interneuron synapsesThese studies suggest a complex interplay by Ca2+ entry via CP-AMPARs, NMDARs, and pre- and postsynaptic mGluRs to trigger either LTD or LTP all modulated by modest changes in postsynaptic membrane potential.
“Taken together, these studies suggest a complex interplay by Ca2+ entry via CP-AMPARs, NMDARs, and pre- and postsynaptic mGluRs to trigger either LTD or LTP all modulated by modest changes in postsynaptic membrane potential.”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesPharmacological block of either perisynaptic mGluR1 or mGluR5 prevents this Hebbian form of LTP; exogenous application of either mGluR1 or mGluR5 agonists alone is insufficient to induce LTP, suggesting that convergent activity via CP-AMPARs and mGluRs are required for its induction.
“Pharmacological block of either perisynaptic mGluR1 or mGluR5 prevents this Hebbian form of LTP; however, exogenous application of either mGluR1 or mGluR5 agonists alone is insufficient to induce LTP, suggesting that convergent activity via CP-AMPARs and mGluRs are required for its induction (447).”
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Premisecitation§ 2. Interneuron targets of CCK-expressing cellsGABAAR-mediated IPSCs can be elicited on PV cells by CCK interneuron activity in CA1 and dentate gyrus and possess the archetypal asynchronicity.
“Indeed, GABAAR-mediated IPSCs can be elicited on PV cells by CCK interneuron activity in both these regions (506, 980, 1257) and possess the archetypal asynchronicity (506).”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsGABAAR responses can be observed between PVBCs and AACs but due to their lack of connectivity never in the reverse direction.
“GABAAR responses can be observed between PVBCs and AACs but due to their lack of connectivity never in the reverse direction (594).”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsIn hippocampus, PVBCs provide GABAAR inhibition onto each other, whereas there is no such connectivity between their AAC counterparts.
“In hippocampus, PVBCs provide GABAAR inhibition onto each other (65, 211, 258, 594, 980, 1257), whereas there is no such connectivity between their AAC counterparts (594).”
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Premisecitation§ 4. Mossy fiber-dentate gyrus basket cell synapsesIn hippocampus, CGE-derived interneurons comprise both CCK- and VIP-containing interneurons and largely reside in the CA1 s.r., consistent with those cells that express the NMDAR-dependent LTP.
“In hippocampus, CGE-derived interneurons comprise both CCK- and VIP-containing interneurons and largely reside in the CA1 s.r. (763), consistent with those cells that express the NMDAR-dependent LTP.”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsIn DG, PVBCs mediate GABAAR responses onto CCK HICAP cells, but functional evidence of an analogous connection in CA1 is yet to be described.
“In DG, PVBCs mediate GABAAR responses onto CCK HICAP cells (980), but functional evidence of an analogous connection in CA1 is yet to be described.”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsInhibiting PV interneuron activity increases the firing rate of BiCs, resulting in a switch from perisomatic to dendritic inhibition of CA1 PCs.
“Inhibiting PV interneuron activity increases the firing rate of BiCs, resulting in a switch from perisomatic to dendritic inhibition of CA1 PCs (703).”
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Premisecitation§ VII. GABA RECEPTORSGABA exerts its cellular actions predominantly via ionotropic GABAA receptors and metabotropic GABABRs.
“GABA exerts its cellular actions predominantly via the ionotropic GABAA receptors (GABAARs) and metabotropic GABABRs (863).”
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Premisecitation§ 4. Interneuron targets of NGFCsModeling of networks consisting of interconnected interneurons mediating GABAA,slow and GABAA,fast is sufficient to produce theta and gamma rhythms, thus implicating NGFC cross-talk to other interneuron subtypes in such network phenomenon.
“Modeling of networks consisting of interconnected interneurons mediating GABAA,slow and GABAA,fast is sufficient to produce theta and gamma rhythms, thus implicating NGFC cross-talk to other interneuron subtypes in such network phenomenon (1199).”
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Premisecitation§ 2. Interneuron targets of CCK-expressing cellsGABAAR-mediated inhibitory transmission between homologous pairs of CCKBCs, CCK SCAs, and CCK HICAPs have all been identified.
“GABAAR-mediated inhibitory transmission between homologous pairs of CCKBCs (258, 594), CCK SCAs (19, 21), and CCK HICAPs (980) have all been identified.”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsA subpopulation of entorhinal cortical interneurons, some of which express PV, send long-range inhibitory projections into the hippocampus and elicit GABAAR-mediated responses onto various hippocampal interneurons.
“Interestingly, a subpopulation of entorhinal cortical interneurons, some of which express PV, send long-range inhibitory projections into the hippocampus and elicit GABAAR-mediated responses onto various hippocampal interneurons (69, 781).”
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Premisecitation§ 3. Interneuron targets of SST-expressing cellsDisinhibition of CA1 NGFCs by O-LM interneurons modulates the balance between feed-forward and feedback inhibition of the distal dendrites of PCs, revealing a role for interneuron connectivity in gating modes of inhibition onto PCs.
“Furthermore, the disinhibition of CA1 NGFCs by O-LM interneurons modulates the balance between feed-forward and feedback inhibition of the distal dendrites of PCs (299), revealing a role for interneuron connectivity in gating modes of inhibition onto PCs.”
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Premisecitation§ 4. Interneuron targets of NGFCsNGFCs express high levels of α1 subunit, and the GABAAR-mediated responses impinging on this subtype are sensitive to low nanomolar concentrations of zolpidem.
“Like PV-expressing interneurons, NGFCs express high levels of α1 subunit, and unsurprisingly, the GABAAR-mediated responses impinging on this subtype are sensitive to low nanomolar concentrations of zolpidem (367, 550).”
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Premisecitation§ 4. Interneuron targets of NGFCsIn CA1, NGFCs and their related IvCs are the most abundant subgroup of interneurons and are distributed in the s.l.m., s.r., and s.p. layers.
“In CA1, NGFCs and their related IvCs (366) are the most abundant subgroup (102) of interneurons and are distributed in the s.l.m., s.r., and s.p. layers (see sect. IIG).”
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Premisecitation§ 3. Interneuron targets of SST-expressing cellsManipulations of SST interneuron activity can modulate the rate and precision of PVBC firing, likely influencing information flow through the dentate gyrus.
“Manipulations of SST interneuron activity can modulate the rate and precision of PVBC firing (980), likely influencing information flow through the dentate gyrus.”
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Premisecitation§ 4. Interneuron targets of NGFCsIn CA1 and dentate gyrus, NGFCs/IvCs have been shown to mediate GABAA,slow on unidentified s.l.m. and molecular layer interneurons, respectively.
“although in CA1 and dentate gyrus they have been shown to mediate GABAA,slow on unidentified s.l.m. and molecular layer interneurons, respectively (48, 926).”
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Premisecitation§ 1. Interneuron targets of PV-expressing cellsFunctional GABAAR-mediated inhibitory inputs are observed onto BiCs and O-LM interneurons with a higher synaptic strength onto the former.
“Functional GABAAR-mediated inhibitory inputs are observed onto BiCs and O-LM interneurons with a higher synaptic strength onto the former (703).”
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Premisecitation§ 2. Interneuron targets of CCK-expressing cellsDisruption of CCK interneuron firing results in decreased inhibitory drive onto these postsynaptic targets altering the temporal characteristics of PV interneuron firing.
“Disruption of CCK interneuron firing results in decreased inhibitory drive onto these postsynaptic targets altering the temporal characteristics of PV interneuron firing (506).”
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Premisecitation§ 5. Interneuron specific cellsISI-3 cells located in s.p. and s.r. possess a relatively high connectivity to O-LM interneurons whilst providing no input onto principal cells.
“Employing transgenic reporter mice and conditional optogenetic expression strategies, ISI-3 cells located in s.p. and s.r. possess a relatively high connectivity to O-LM interneurons (185, 1145) whilst providing no input onto principal cells (1145).”
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Premisecitation§ 5. Interneuron specific cellsTHIP-mediated currents are present in dentate gyrus PV-containing but not other DG interneurons including HIPP and other SST-containing interneuron populations.
“In agreement with the selective expression of δ subunits in certain hippocampal interneuron subtypes, THIP-mediated currents are present in dentate gyrus PV-containing but not other DG interneurons including HIPP and other SST-containing interneuron populations (1109, 1160, 1256).”
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Premisecitation§ 5. Interneuron specific cellsEctopic expression of the δ-subunit in SST HIPP cells results in the presence of GABAARs containing this subunit at nonsynaptic locations, including perisynaptic sites near symmetric synapses and an emergence of THIP sensitivity.
“Ectopic expression of the δ-subunit in SST HIPP cells results in the presence of GABAARs containing this subunit at nonsynaptic locations, including perisynaptic sites near symmetric synapses and an emergence of THIP sensitivity (1109).”
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Premisecitation§ 5. Interneuron specific cellsExtrasynaptic GABAAR subunits are highly expressed in dentate granule cells and in hippocampal interneurons.
“Extrasynaptic GABAAR subunits are highly expressed in dentate granule cells and in hippocampal interneurons (893).”
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Premisecitation§ 5. Interneuron specific cellsIn unidentified CA1 interneurons of the s.r., tonic inhibition is biphasic resulting in an increase or decrease in action potential output due to depolarizing and shunting responses, respectively, that are in turn dependent on the conductance level of tonic inhibition.
“For example, in unidentified CA1 interneurons of the s.r., tonic inhibition is biphasic resulting in an increase or decrease in action potential output due to depolarizing and shunting responses, respectively, that are in turn dependent on the conductance level of tonic inhibition (1038).”
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Premisecitation§ 5. Interneuron specific cellsIn DG, removal of the δ subunit increases inhibitory input onto granule cells and reduces the susceptibility to kainate-induced seizures.
“In DG, removal of this subunit increases inhibitory input onto granule cells and reduces the susceptibility to kainate-induced seizures (659).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [659] source
Not checked in the free run.
May combine two claims.
Premisecitation§ 5. Interneuron specific cellsTHDOC-mediated effects are seen in interneuron subtypes expressing δ such as NGFCs and PV interneurons with little or no effect in SST cells that are devoid of this subunit.
“Thus THDOC-mediated effects are seen in interneuron subtypes expressing δ such as NGFCs and PV interneurons (316, 320, 788, 858, 1256) with little or no effect in SST cells that are devoid of this subunit (1160).”
Quote in the paperNot a substantial claim0 of 6 sources checkedMay combine two claims.
Premisecitation§ 5. Interneuron specific cellsAlthough the neurosteroid binding site is located between α and β subunits, it is the δ subunit that generally dictates sensitivity to these neurosteroids.
“Although the binding site is located between α and β subunits (498), it is the δ subunit that generally dictates sensitivity to these neurosteroids (629).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ 5. Interneuron specific cellsThis interaction paces O-LM interneuron output, modulating their firing rate and timing with implications for dendritic electrogenesis, burst firing in PCs, and the generation of oscillatory activity.
“This interaction paces O-LM interneuron output, modulating their firing rate and timing with implications for dendritic electrogenesis, burst firing in PCs, and the generation of oscillatory activity (703, 1145).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ 5. Interneuron specific cellsAlthough GABAARs are prevalent at synaptic sites, a significant population exists at peri- and extrasynaptic locations.
“Although GABAARs are prevalent at synaptic sites, a significant population exists at peri- and extrasynaptic locations.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ 5. Interneuron specific cellsConditional δ ablation specifically from PV-expressing interneurons increases the frequency of γ oscillatory activity in the CA3, illustrating a negative modulation of such oscillatory activity by tonic inhibition.
“Conditional δ ablation specifically from PV-expressing interneurons increases the frequency of γ oscillatory activity in the CA3, illustrating a negative modulation of such oscillatory activity by tonic inhibition (320, 739).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationcitation§ 5. Interneuron specific cellsThis additional dialogue provides an alternative long-range mode of disinhibition to that locally imparted by ISI-3 cells which together modulate the function of O-LM cells.
“This additional dialogue provides an alternative long-range mode of disinhibition to that locally imparted by ISI-3 cells which together modulate the function of O-LM cells (185).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [185] source
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Premisecitation§ 5. Interneuron specific cellsThe targeting of SST interneurons by VIP cells appears to be a generalized motif across brain structures including somatosensory, visual, and auditory cortices, and this specific disinhibitory microcircuit is important in sensory processing that, in some circumstances, demonstrates behavioral state dependence.
“The targeting of SST interneurons by VIP cells appears to be a generalized motif across brain structures including somatosensory, visual, and auditory cortices, and this specific disinhibitory microcircuit is important in sensory processing that, in some circumstances, demonstrates behavioral state dependence (363, 553, 660, 905, 906, 908, 1246, 1270).”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [363] source
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- cites [553] source
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- cites [660] source
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- cites [905] source
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- cites [906] source
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- cites [908] source
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- cites [1246] source
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- cites [1270] source
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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone given§ C. GABAB Receptor-Mediated InhibitionSpecific connectivity rules exist serving discrete network functions.
“Although this intercommunication has the potential to be widespread, it is clear that specific connectivity rules exist serving discrete network functions.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisenone given§ C. GABAB Receptor-Mediated InhibitionPVBCs innervate the soma and first 20-30 μm of the proximal dendrites of principal cells, and AACs target the pyramidal neuron axon initial segment.
“PVBCs innervate the soma and first 20–30 μm of the proximal dendrites of principal cells, and AACs target the pyramidal neuron axon initial segment (FIGURE 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone given§ C. GABAB Receptor-Mediated InhibitionGABABRs are heterodimers of seven transmembrane G protein (Gi/Go)-linked proteins that are comprised of a GABAB1 and a GABAB2 subunit.
“In contrast to the ligand-gated GABAA receptors, GABABRs are heterodimers of seven transmembrane G protein (Gi/Go)-linked proteins that are comprised of a GABAB1 (either GABAB1a or GABAB1b) and a GABAB2 subunit.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionPVBCs of the dentate gyrus, but not their dendrite-targeting counterparts, express functional postsynaptic GABABRs.
“PVBCs of the dentate gyrus, but not their dendrite-targeting counterparts, express functional postsynaptic GABABRs (116) (FIGURE 18).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [116] source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ C. GABAB Receptor-Mediated InhibitionOngoing activity of SST interneurons in the somatosensory cortex was shown to mediate depression of glutamate release from pyramidal cells via presynaptic GABABR activation.
“More recently, ongoing activity of SST interneurons in the somatosensory cortex was shown to mediate depression of glutamate release from pyramidal cells via presynaptic GABABR activation (1154).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1154] source
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Premisecitation§ C. GABAB Receptor-Mediated InhibitionIn general, postsynaptic GABABR activation occurs via spillover of GABA from the synapse that in experimental paradigms requires either strong electrical stimulation/trains of stimuli resulting in GABA release from multiple neurons to overcome GABA uptake mechanisms or stimulation under conditions where GABA uptake is pharmacologically blocked.
“In general, postsynaptic GABABR activation occurs via spillover of GABA from the synapse that in experimental paradigms requires either strong electrical stimulation/trains of stimuli resulting in GABA release from multiple neurons to overcome GABA uptake mechanisms or stimulation under conditions where GABA uptake is pharmacologically blocked (427, 523, 982).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone given§ C. GABAB Receptor-Mediated InhibitionThe vast majority of excitatory synapses onto pyramidal cells are made onto spines located on the mid proximal to distal dendritic portions of the cell.
“The vast majority of excitatory synapses onto pyramidal cells are made onto spines located on the mid proximal to distal dendritic portions of the cell.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionProximal inhibition alters the electrotonic properties (shunting) of the path between the excitatory conductance input and the axon initial segment output, increasing threshold and decreasing the maximal firing rate for a given excitatory conductance input.
“however, proximal inhibition alters the electrotonic properties (i.e., shunting) of the path between the excitatory conductance input and the axon initial segment output to both increase threshold and decrease the maximal firing rate for a given excitatory conductance input.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [924] source
Not checked in the free run.
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Premisecitation§ C. GABAB Receptor-Mediated InhibitionSuch modulatory mechanisms occur on various interneuron subtypes resulting in decreased GABA output at synapses onto both excitatory and inhibitory neurons, the former providing another synaptic route for disinhibition.
“Such modulatory mechanisms occur on various interneuron subtypes resulting in decreased GABA output at synapses onto both excitatory and inhibitory neurons (116, 478, 916), the former providing another synaptic route for disinhibition.”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionDynamic modulation of such interactions serves to gate the mode and timing of inhibition impinging on principal cells, hence sculpting their input/output relationships central for synaptic plasticity induction/expression and generation of network oscillations.
“Dynamic modulation of such interactions serves to gate the mode and timing of inhibition impinging on principal cells, hence sculpting their input/output relationships central for synaptic plasticity induction/expression and generation of network oscillations.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionThis form of disinhibition can result in hyperexcitability of principal cells and may play a part in pathological discharges akin to those seen in epilepsy.
“On the other hand, this form of disinhibition can result in hyperexcitability of principal cells (345, 808, 809) and may play a part in pathological discharges akin to those seen in epilepsy.”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionNot all interneuron subtypes exhibit postsynaptic GABABR responses, and a division of labor between subtypes in providing putative GABAAR- or GABABR-mediated IPSPs indicates the presence of selective microcircuits responsible for activation of postsynaptic GABABRs.
“Not all interneuron subtypes exhibit postsynaptic GABABR responses, and a division of labor between subtypes in providing putative GABAAR- or GABABR-mediated IPSPs (628, 993) indicates the presence of selective microcircuits responsible for activation of postsynaptic GABABRs.”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionPerisomatic inhibition efficiently controls Na+-dependent action potential generation, whereas dendritic inhibition influences local voltage-gated conductances, shunts excitatory inputs lying distal to their location, and regulates the generation of Ca2+-dependent action potentials and synaptic plasticity.
“Perisomatic inhibition efficiently controls Na+-dependent action potential generation, whereas dendritic inhibition influences local voltage-gated conductances, shunts excitatory inputs lying distal to their location, and regulates the generation of Ca2+-dependent action potentials and synaptic plasticity (522, 790, 721).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionThe radial extent of single VIP-cell disinhibition of SOM-interneuron driven lateral inhibition is ~120 μm, consistent with the known axonal arborization of VIP-containing inhibitory neurons.
“The radial extent of single VIP-cell disinhibition of SOM-interneuron driven lateral inhibition is ~120 μm, which is consistent with the known axonal arborization of VIP-containing inhibitory neurons (569).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [569] source
Not checked in the free run.
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Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionBecause NGFCs release GABA in a hybrid manner with features of both synchronous and volume transmission, large areas of the hippocampal dendritic landscape could become bathed in GABA, yielding massive indiscriminant inhibition and suggesting a more permissive binary role for inhibition in sculpting excitation than one designed around its timing.
“Given that NGFCs release GABA in a hybrid manner with features of both synchronous and volume transmission (see sect. IVL3), large areas of the hippocampal dendritic landscape could become bathed in GABA yielding massive indiscriminant inhibition, suggesting a more permissive binary role for inhibition in sculpting excitation than one designed around its timing.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionThis differential inhibitory input provides two integration windows for EPSP summation, with a broader integration window for EPSPs arriving at dendritic sites.
“This differential inhibitory input provides two integration windows for EPSP summation with a broader integration window existing for EPSPs arriving at dendritic sites.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionSuch a mechanism whereby small numbers of VIP-containing interneurons disinhibit "pockets" of principal cells provides an attractive mechanism to permit transient activation of precise selective circuits within normally inhibited cortical circuits.
“Such a mechanism whereby small numbers of VIP-containing interneurons disinhibit “pockets” of principal cells provides an attractive mechanism to permit transient activation of precise selective circuits within normally inhibited cortical circuits.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionVIP-containing interneurons selectively target other inhibitory interneurons, with SST-containing interneurons serving as a primary target, while principal cells are largely spared VIP-containing interneuron input.
“VIP-containing interneurons selectively target other inhibitory interneurons (see sect. IIH) with SST-containing interneurons serving as a primary target, while principal cells are largely spared VIP-containing interneuron input (553, 652, 906).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionIn somatosensory cortex, both EPSCs and feedforward IPSCs depress in response to repetitive stimulation, but the depression is greater for inhibition than excitation, resulting in increased action potential jitter and loss of temporal precision.
“For example, in somatosensory cortex, although both EPSCs and feedforward IPSCs depress in response to repetitive stimulation, the magnitude of the depression is greater for inhibition than excitation resulting in an increased action potential jitter and a loss of temporal precision (372).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [372] source
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Premisecitation§ C. GABAB Receptor-Mediated InhibitionThe bulk of feedforward inhibitory inputs arise through perisomatic fast spiking basket cells, and inhibition onto dendritic compartments is modest by comparison.
“Pouille and Scanziani (922) elegantly demonstrated that the bulk of feedforward inhibitory inputs arise through perisomatic fast spiking basket cells and that inhibition onto dendritic compartments was modest by comparison.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [922] source
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Premisecitation§ VIII. ENDOCANNABINOIDSCB1R is mainly located at synaptic terminals on principal cells and interneurons in the hippocampus.
“mainly located at synaptic terminals on PCs and interneurons in the hippocampus (559, 560, 754).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ C. GABAB Receptor-Mediated InhibitionIn CA3 pyramidal cells, erosion of feedforward inhibitory input does not lead to loss of temporal precision of action potential generation, but can trigger prolonged plateau depolarization following action potential firing.
“Of interest, in contrast to other cortical circuits, erosion of this feedforward inhibitory input does not lead to a loss of temporal precision of action potential generation in CA3 pyramidal cells, but can trigger a prolonged plateau depolarization following action potential firing (1114).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1114] source
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May combine two claims.
Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionThe rapid depression of excitatory drive onto this interneuron population ensures that they are active for only short periods, providing a coincidence detection mode of inhibitory control.
“The rapid depression of excitatory drive onto this interneuron population ensures that they are active for only short periods, providing a coincidence detection mode of inhibitory control.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionRecruitment of PV- versus SST-mediated blanket inhibition would have significantly different temporal dynamics with distinct influences on cortical information processing.
“In keeping with the discussion above, one can envision that recruitment of PV- versus SST-mediated blanket inhibition would have significantly different temporal dynamics with distinct influences on cortical information processing (see sects. IIB and IIII for further discussion).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ C. GABAB Receptor-Mediated InhibitionIn many cortical circuits, lateral inhibition is thought to sharpen stimulus selectivity by sharpening the tuning of neuronal receptive fields in a cell type and circuit specific manner.
“In many cortical circuits, lateral inhibition is thought to sharpen stimulus selectivity by sharpening the tuning of neuronal receptive fields in a cell type and circuit specific manner (522).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [522] source
Not checked in the free run.
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Premisecitation§ C. GABAB Receptor-Mediated InhibitionIn CA1 hippocampus, the vast majority of NGFCs are located within the s.l.m., where they appear to tile the entire extent of the region to cover the distal dendrites of principal cells.
“In the CA1 hippocampus, the vast majority of NGFCs are located within the s.l.m., where they appear to tile the entire extent of the region to cover the distal dendrites of principal cells (1137, 1138).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ VIII. ENDOCANNABINOIDSAnandamide and 2-AG are partial and full CB1R agonists, respectively, with 2-AG present at much higher concentrations and therefore the major known contributor to eCB signaling in the brain.
“Anandamide and 2-AG are partial and full CB1R agonists, respectively, with the latter being present at much higher concentrations and therefore is the major known contributor to eCB signaling in the brain (1053).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1053] source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ VIII. ENDOCANNABINOIDSThe endogenous cannabinoid (eCB) system primarily consists of the lipid-derived messengers anandamide and 2-AG, which exert cellular actions through two major receptor subtypes, CB1R and CB2R.
“The endogenous cannabinoid (eCB) system primarily consists of the lipid-derived messengers N-arachidonoyl-ethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG) that exert their cellular actions through two major receptor subtypes, CB1R and CB2R (17, 272).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ VIII. ENDOCANNABINOIDSCB1R is one of the most highly expressed G protein-coupled receptors in the CNS.
“The CB1R is one of the most highly expressed G protein-coupled receptors in the CNS (485, 486)”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [485] Herkenham M, 1991, NIDA Res Monogr
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Interpretationreasoning§ C. GABAB Receptor-Mediated InhibitionBecause the s.l.m. is the target subfield for excitatory afferents from both the temporoammonic entorhinal cortex and thalamic nucleus reuniens, such blanket inhibition could act to shunt the distal dendrites of principal cells, functioning as a gate to block entorhinal/thalamic input and favoring activity arising through the Schaffer collateral pathway into s.r.
“Given that the s.l.m. is the target subfield for excitatory afferents from both the temporoammonic entorhinal cortex and thalamic nucleus reuniens, such blanket inhibition could act to shunt the distal dendrites of principal cells functioning as a gate to block entorhinal/thalamic input and favoring activity arising through the Schaffer collateral pathway into s.r.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ VIII. ENDOCANNABINOIDSCB1R and CB2R are predominantly expressed in the brain and immune system, respectively.
“These G protein-coupled receptors are predominantly expressed in the brain and immune system, respectively (727).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [727] source
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The authors state this as an assumption.
Interneurons account for 11% of the total neuronal population in CA1.
“assuming interneurons account for 11% of the total neuronal population (102)”
The authors state this as an assumption.
MGE-derived interneurons account for ~60% of all CA1 interneurons, with relative contributions of 35/25/40% from PV, somatostatin, and neurogliaform/Ivy interneuron cohorts, respectively.
“With the assumption that MGE-derived interneurons account for ~60% of all CA1 interneurons with relative contributions of 35/25/40% from PV, somatostatin, and neurogliaform/Ivy interneuron cohorts, respectively”
The authors state this as an assumption.
CGE-derived interneurons account for ~40% of all CA1 interneurons, with relative contributions of 30/30/25/10% from CCK+ interneurons, interneuron selective interneurons, neurogliaform interneurons, SST+ interneurons, respectively, and a remaining 5% of unidentified interneurons.
“Assuming that CGE-derived interneurons account for ~40% of all CA1 interneurons with relative contributions of 30/30/25/10% from CCK+ interneurons, interneuron selective interneurons, neurogliaform interneurons, SST+ interneurons, respectively, and a remaining 5% of unidentified interneurons”
The paper relies on this without support.
No study has tackled an extensive characterization of the biophysical properties of Ca2+ channel types in particular interneuron subtypes.
“Surprisingly, no study has tackled an extensive characterization of the biophysical properties of any of these channel types in particular subtypes of interneurons; therefore, it is unclear whether Ca2+ channel properties are similar or distinct from those of hippocampal principal cells.”
The authors state this as an assumption.
Extracellular acidification during seizures activates ASIC channels on both principal and inhibitory interneurons.
“Given that seizures trigger an extracellular acidification, it is not unreasonable to assume that this acidification activates ASIC channels on both principal and inhibitory interneurons.”
The paper relies on this without support.
In the CA1 hippocampus, excitatory afferents of both intrahippocampal and subcortical origins target both excitatory and inhibitory neurons.
“In the CA1 hippocampus, excitatory afferents (of both intrahippocampal and subcortical origins) target both excitatory and inhibitory neurons.”
The paper relies on this without support.
The output features of principal cells, spike frequency and timing, are critical for correct cortical functioning and are regulated by recurrent excitatory drive onto interneurons that then target the same principal cell populations.
“The output features of principal cells, i.e., spike frequency and timing, are critical for correct cortical functioning and are regulated by recurrent excitatory drive onto interneurons that then target the very same principal cell populations.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Although all deep NGCs belong to the Lamp5 subclass, some are derived from the CGE and some from the MGE, as in the hippocampus.
“Our results suggest that although all deep NGCs belong to the Lamp5 subclass, some are derived from the CGE and some from the MGE, as in the hippocampus25–27.”
From Phenotypic variation of transcriptomic cell types in mouse motor cortex (2021) · cites this paper as [26]
The Lamp5 Lhx6 supertype is likely derived from MGE instead of CGE.
“is likely derived from MGE instead of CGE (Pelkey et al., 2017)”
From A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation (2021) · cites this paper as Pelkey et al., 2017
Isocortical and hippocampal GABAergic interneuron types are organized by their embryonic origins, firing characteristics, and local connectivity patterns.
“Isocortical and hippocampal GABAergic interneuron types are similarly organized by their embryonic origins, firing characteristics and local connectivity patterns”
From A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation (2021) · cites this paper as Pelkey et al., 2017
The taxonomy is also consistent with the large body of literature on cortical GABAergic interneurons and with the authors' Patch-seq study, with MET types corresponding well with the supertypes defined here.
“It is also consistent with the large body of literature on cortical GABAergic interneurons (Lim et al., 2018; Pelkey et al., 2017; Tremblay et al., 2016), and our Patch-seq study (Gouwens et al., 2020) with MET types defined in that study corresponding well with the supertypes defined here”
From A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation (2021) · cites this paper as Pelkey et al., 2017
For some time after action potential capability emerges, new granule cells exhibit excitatory instead of inhibitory responses to typically inhibitory neurotransmitter GABA, suggesting they are more likely to fire than mature granule cells.
“For some time thereafter, new granule cells exhibit excitatory instead of inhibitory responses to typically inhibitory neurotransmitter GABA (Chancey et al., 2013), suggesting that these cells are more likely to fire than mature granule cells, which are strongly inhibited (Amaral et al., 2007; Pelkey et al., 2017).”
From Adult neurogenesis, glia, and the extracellular matrix (2019) · cites this paper as Pelkey et al., 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Cluster 4 and 5 time constants disagree with Table 1
MinorThe text gives time constants of 57 and 5 ms for clusters 4 and 5, respectively; Table 1 gives 44 and 38 ms.
“Cells in clusters 4 and 5 had similar electrophysiological properties with high input resistances (430 and 401 MΩ, respectively) and slow membrane time constants (57 and 5 ms, respectively).”
“Time constant, ms 13 ± 8 46 ± 18 25 ± 8 44 ± 15 38 ± 13 22 ± 9”
Axo-axonic cells' share of all CA1 neurons is understated
MinorThe paper estimates about 1,500 axo-axonic cells among 350,000 CA1 neurons. That is about 0.43% of CA1 neurons, not 0.04%.
Reported 0.04 · recomputed 0.428571
“Axo-axonic cells (AACs) are estimated to make up ~4% (~1,500 cells) of CA1 hippocampal interneurons, thus representing 0.04% of all CA1 neurons assuming interneurons account for 11% of the total neuronal population (102).”
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Robust decomposition of cell type mixtures in spatial transcriptomics
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A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation
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Self-citationPhenotypic variation of transcriptomic cell types in mouse motor cortex
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Functionally Distinct Neuronal Ensembles within the Memory Engram
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Probabilistic cell typing enables fine mapping of closely related cell types in situ
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Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics
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“distinct connectivity, firing patterns, and molecular content (Bezaire and Soltesz, 2013; Freund and Buzsaki, 1996; Klausberger and Somogyi, 2008; Pelkey et al., 2017; Somogyi, 2010; Wheeler et al., 2015).”
Inhibitory Interneurons Regulate Temporal Precision and Correlations in Cortical Circuits
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Adult neurogenesis, glia, and the extracellular matrix
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An emerging circuit pharmacology of GABAA receptors
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“For recent reviews on interneurons see [144] for cortical interneurons and [145] for hippocampal interneurons.”
BackgroundTuri, G. F., Li, W.-K., Chavlis, S., Pandi, I., O’Hare, J., Priestley, J. B., Grosmark, A. D., Liao, Z., Ladow, M., Zhang, J. F., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.01.009 · Cited by 218 · see citing works
Ayhan, F., Kulkarni, A., Berto, S., Sivaprakasam, K., Douglas, C., Lega, B. C., & Konopka, G. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.003 · Cited by 198 · see citing works
Interneuron Types as Attractors and Controllers
Fishell, G., & Kepecs, Á. (2019) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-070918-050421 · Cited by 197 · see citing works
“…more thoroughly (Cardin 2018, Feldmeyer et al. 2018, Khan et al. 2018, Lovett-Barron & Losonczy 2014, Lucas & Clem 2018, Naka & Adesnik 2016, Pelkey et al. 2017, Roux & Buzsaki 2015, Urban-Ciecko & Barth 2016, Wood et al. 2017, Yavorska & Wehr 2016), and our brief overview simply…”
BackgroundUdakis, M., Pedrosa, V., Chamberlain, S. E. L., Claudia Clopath, A., & Mellor, J. R. (2020) · Nature Communications · doi:10.1038/s41467-020-18074-8 · Cited by 195 · see citing works
“This is important since distinct interneuron subtypes play highly specific roles within neuronal networks (Pelkey et al., 2017) and therefore plasticity at one inhibitory synapse may have very different effects to another.”
BackgroundInfluentialInhibitory stabilization and cortical computation
Sadeh, S., & Clopath, C. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-00390-z · Cited by 183 · see citing works
Morphological diversity and connectivity of hippocampal interneurons
Booker, S. A., & Vida, I. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2882-2 · Cited by 210 · see citing works
“INs are central to our understanding of circuit function and while they have been reviewed previously (Amaral et al. 2007; Freund and Buzsáki 1996; Klausberger 2009; Pelkey et al. 2017), these reviews have not taken into account the full complexity and connectivity of all known subtypes.”
Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms
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Geiller, T., Vancura, B., Terada, S., Troullinou, E., Chavlis, S., Tsagkatakis, G., Tsakalides, P., Ócsai, K., Poirazi, P., Rózsa, B. J., et al. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.013 · Cited by 159 · see citing works
“To show that this increase was the remnant representation of the old reward zone, we split the recording session in half and observed that SomC and BiC activity levels gradually decreased and increased in the old and current reward zones, respectively (Figure 6H).”
InfluentialThe role of gamma oscillations in central nervous system diseases: Mechanism and treatment
Guan, A., Wang, S., Huang, A., Qiu, C., Li, Y., Li, X., Jinfei, W., Wang, Q., & Deng, B. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.962957 · Cited by 164 · see citing works
“The frequency of gamma oscillations is determined primarily by GABAA receptor-induced inhibitory postsynaptic currents (IPSCs; Buzsáki and Wang, 2012; Takada et al., 2014; Pelkey et al., 2017; Antonoudiou et al., 2020).”
BackgroundAlternating sources of perisomatic inhibition during behavior
Dudok, B., Klein, P., Hwaun, E., Lee, B. R., Yao, Z., Fong, O., Bowler, J. C., Terada, S., Sparks, F. T., Szabo, G. G., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.01.003 · Cited by 161 · see citing works
“Such a disinhibitory role is well known for hippocampal VIP- or calretininexpressing INs (Klausberger and Somogyi, 2008; Pelkey et al., 2017).”
Preserving the balance: diverse forms of long-term GABAergic synaptic plasticity
Chiu, C.-Y. Q., Barberis, A., & Higley, M. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0141-5 · Cited by 137 · see citing works
Functions of adult-born neurons in hippocampal memory interference and indexing
Miller, S. M., & Sahay, A. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0484-2 · Cited by 146 · see citing works
STalign: Alignment of spatial transcriptomics data using diffeomorphic metric mapping
Clifton, K., Anant, M. M.-G., Aihara, G., Atta, L., Aimiuwu, O. K., Kebschull, J. M., Miller, M. I., Tward, D. J., & Fan, J. (2023) · Nature Communications · doi:10.1038/s41467-023-43915-7 · Cited by 139 · see citing works
Robust decomposition of cell type mixtures in spatial transcriptomicsPreprint
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Hippocampal GABAergic interneurons and memory
Tzilivaki, A., Tukker, J. J., Maier, N., Poirazi, P., Sammons, R. P., & Schmitz, D. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.016 · Cited by 145 · see citing works
Petrache, A. L., Rajulawalla, A., Shi, A., Wetzel, A., Saito, T., Saido, T. C., Harvey, K., & Ali, A. B. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz016 · Cited by 124 · see citing works
“As GABAergic cells are highly diverse in their properties and synapse on specific postsynaptic subcellular domains, (Maccaferri and Lacaille 2003; Markram et al. 2004; Ascoli et al. 2008; Klausberger and Somogyi 2008; Pelkey et al. 2017) even subtle disruption in interneuron behavior could unequivocally impact glutama…”
BackgroundTop-down control of hippocampal signal-to-noise by prefrontal long-range inhibition
Malik, R., Li, Y., Schamiloglu, S., & Sohal, V. S. (2022) · Cell · doi:10.1016/j.cell.2022.04.001 · Cited by 138 · see citing works
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 130 · see citing works
Local Feedback Inhibition Tightly Controls Rapid Formation of Hippocampal Place Fields
Rolotti, S. V., Ahmed, M. S., Szoboszlay, M., Geiller, T., Negrean, A., Blockus, H., Gonzalez, K. C., Sparks, F. T., Canales, A. S. S., Tuttman, A. L., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.12.003 · Cited by 114 · see citing works
Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor
Mikulovic, S., Restrepo, C. E., Siwani, S., Bauer, P., Pupe, S., Tort, A. B. L., Kullander, K., & Leão, R. N. (2018) · Nature Communications · doi:10.1038/s41467-018-05907-w · Cited by 114 · see citing works
A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation
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“Hippocampal and isocortical GABAergic interneuron types exhibit similar molecular, anatomical, and physiological properties (Pelkey et al., 2017; Tremblay et al., 2016).”
Stress during critical periods of development and risk for schizophrenia
Gomes, F. V., Zhu, X., & Grace, A. A. (2019) · Schizophrenia Research · doi:10.1016/j.schres.2019.01.030 · Cited by 126 · see citing works
“, 2015), and PVI dysregulation can potentially cause Hipp dysfunction (Pelkey et al., 2017) that is commonly associated with schizophrenia (Lieberman et al.”
BackgroundHow development sculpts hippocampal circuits and function
Cossart, R., & Khazipov, R. (2021) · Physiological Reviews · doi:10.1152/physrev.00044.2020 · Cited by 119 · see citing works
Gómez de San José, N., Massa, F., Halbgebauer, S., Oeckl, P., Steinacker, P., & Otto, M. (2022) · Journal of Neural Transmission · doi:10.1007/s00702-021-02411-2 · Cited by 112 · see citing works
Communication, Cross Talk, and Signal Integration in the Adult Hippocampal Neurogenic Niche
Vicidomini, C., Guo, N., & Sahay, A. (2020) · Neuron · doi:10.1016/j.neuron.2019.11.029 · Cited by 107 · see citing works
GABAergic interneurons in epilepsy: More than a simple change in inhibition
Marafiga, J. R., Pasquetti, M. V., & Calcagnotto, M. E. (2020) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2020.106935 · Cited by 107 · see citing works
Cortico-Limbic Interactions Mediate Adaptive and Maladaptive Responses Relevant to Psychopathology
Kovner, R., Oler, J., & Kalin, N. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19101064 · Cited by 94 · see citing works
“While the granule cells of the dentate gyrus and the pyramidal cells of the CA3 and CA1 are excitatory glutamatergic neurons, the hippocampus also contains many different types of GABAergic interneurons (at least 20 different kinds in CA1 alone), providing a glimpse of the complexity of the circuits of the hippocampal…”
BackgroundUchigashima, M., Cheung, A., & Futai, K. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.749164 · Cited by 89 · see citing works
Shisa7 is a GABA A receptor auxiliary subunit controlling benzodiazepine actions
Han, W., Li, J., Pelkey, K. A., Pandey, S., Chen, X., Wang, Y., Wu, K., Ge, L., Li, T., Castellano, D., et al. (2019) · Science · doi:10.1126/science.aax5719 · Cited by 95 · see citing works
Self-citationTargeting S100B Protein as a Surrogate Biomarker and its Role in Various Neurological Disorders
Langeh, U., & Singh, S. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200729100427 · Cited by 101 · see citing works
“Among GABAergic interneurons, are parvalbumin expressed by hippocampal and cortex basket cells, cerebellum purkinje cells, calbindin expressed by purkinje cells of cerebellar, sub-population of hippocampus [35, 40] and outward CA1 pyramidal neurons [41], also cortical populations.”
BackgroundCharacterizing Speed Cells in the Rat Hippocampus
Góis, Z. H. T. D., & Tort, A. B. L. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.054 · Cited by 77 · see citing works
“Inhibitory interneurons are well known to have several functions, such as control of input and output activity of pyramidal cells, generation of oscillatory activity, and segregation of cell assembly sequences (Freund and Buzsáki, 1996; Klausberger and Somogyi, 2008; Pelkey et al., 2017).”
BackgroundCaccavano, A., Bozzelli, P. L., Forcelli, P. A., Pak, D. T. S., Wu, J., Conant, K. E., & Vicini, S. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0425-20.2020 · Cited by 85 · see citing works
Krukowski, K., Nolan, A., Becker, M., Picard, K., Vernoux, N., Frias, E. S., Feng, X., Tremblay, M., & Rosi, S. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.08.210 · Cited by 86 · see citing works
Ghatak, S., Talantova, M. V., McKercher, S. R., & Lipton, S. A. (2020) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-032320-015420 · Cited by 87 · see citing works
Davenport, C. M., Rajappa, R., Katchan, L., Taylor, C. R., Tsai, M., Smith, C. M., de Jong, J. W., Arnold, D. B., Lammel, S., & Krämer, R. (2020) · Neuron · doi:10.1016/j.neuron.2020.09.037 · Cited by 86 · see citing works
“Synaptic inhibition of pyramidal neurons is mediated by several classes of GABAergic interneurons (Pelkey et al., 2017).”
BackgroundDelorme, J. E., Wang, L., Kuhn, F. R., Kodoth, V., Ma, J., Martinez, J. D., Raven, F., Toth, B. A., Balendran, V., Vega-Medina, A., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2019318118 · Cited by 77 · see citing works
“Within the hippocampus, Sst+ interneurons target both neighboring pyramidal cells and other interneuron types (such as Pvalb+ interneurons) for inhibition (28, 43 – 47).”
Naskar, S., Qi, J., Pereira, F., Gerfen, C. R., & Lee, S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108774 · Cited by 72 · see citing works
“Diversity in cortical GABAergic interneurons (INs) is considered to increase the capacity of cortical computation (Fishell and Kepecs, 2019; Pelkey et al., 2017; Tremblay et al., 2016).”
Perez, J. D., Dieck, S. T., Alvarez‐Castelao, B., Tushev, G., Chan, I. C. W., & Schuman, E. M. (2021) · eLife · doi:10.7554/elife.63092 · Cited by 76 · see citing works
“Indeed a better understanding of the subcellular transcriptome of these neurons may help explain their diverse size, transmitter phenotype, axonal and dendritic architecture, and electrophysiological properties (Huang and Paul, 2019; Pelkey et al., 2017).”
BackgroundHollnagel, J., Elzoheiry, S., Gorgas, K., Kins, S., Beretta, C. A., Kirsch, J., Kuhse, J., Kann, O., & Kiss, É. (2019) · PLoS ONE · doi:10.1371/journal.pone.0209228 · Cited by 80 · see citing works
Nguyen, R., Venkatesan, S., Binko, M. A., Bang, J. Y., Cajanding, J. D., Briggs, C., Sargin, D., Imayoshi, I., Lambe, E. K., & Kim, J. C. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1919-19.2020 · Cited by 72 · see citing works
“While being a relatively heterogeneous population, several common features have been described (Armstrong and Soltesz, 2012; Savanthrapadian et al., 2014; Pelkey et al., 2017).”
BackgroundNew insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome
Tiraboschi, E., Martina, S., van der Ent, W., Grzyb, K., Gaweł, K., Cordero-Maldonado, M. L., Poovathingal, S. K., Heintz, S., Satheesh, S. V., Brattespe, J., et al. (2020) · Epilepsia · doi:10.1111/epi.16456 · Cited by 74 · see citing works
Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology
Sakimoto, Y., Oo, P. M.-T., Goshima, M., Kanehisa, I., Tsukada, Y., & Mitsushima, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212456 · Cited by 75 · see citing works
“Gamma-aminobutyric acid (GABA) ergic interneurons contain a conservative estimate of ~38,500 inhibitory interneurons in the CA1 region [2,3].”
BackgroundRegulation of Hippocampal Memory by mTORC1 in Somatostatin Interneurons
Artinian, J., Jordan, A., Khlaifia, A., Honoré, È., Fontaine, A., Racine, A., Laplante, I., & Lacaille, J. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.0728-19.2019 · Cited by 65 · see citing works
“They inhibit the distal temporo-amonic inputs of pyramidal cells in stratum 479 lacunosum-moleculare (9, 17), and send axonal projections in stratum radiatum to inhibit 480 interneurons that, in turn, inhibit SC inputs of pyramidal cells (16).”
BackgroundInfluentialWester, J. C., Mahadevan, V., Rhodes, C. T., Calvigioni, D., Venkatesh, S., Maric, D., Hunt, S., Yuan, X. Q., Zhang, Y., Petros, T. J., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.03.036 · Cited by 66 · see citing works
Self-citationNeuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
“These cells are often classified according to their immunoreactivity against calcium-binding proteins, such as parvalbumin (PV) or calretinin (CR) [117].”
BackgroundGuet-McCreight, A., Skinner, F. K., & Topolnik, L. (2020) · Frontiers in Neural Circuits · doi:10.3389/fncir.2020.00032 · Cited by 64 · see citing works
Hippocampal Somatostatin Interneurons, Long-Term Synaptic Plasticity and Memory
Honoré, È., Khlaifia, A., Bosson, A., & Lacaille, J. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.687558 · Cited by 65 · see citing works
“only represent 10 to 20% of the total neuron population, they can be divided into many subgroups based on their laminar position, dendritic and axonal morphology, protein expression, electrophysiological features, and functions (Freund and Buzsáki, 1996; Somogyi and Klausberger, 2005; Tricoire et al., 2011; Kepecs and…”
BackgroundInfluentialJoffe, M. E., Maksymetz, J., Luchsinger, J. R., Dogra, S., Ferranti, A. S., Luessen, D. J., Gallinger, I. M., Xiang, Z., Branthwaite, H. E., Melugin, P. R., et al. (2022) · Neuron · doi:10.1016/j.neuron.2021.12.027 · Cited by 69 · see citing works
Muscarinic Receptors, from Synaptic Plasticity to its Role in Network Activity
de Sevilla, D. F., Núñez, Á., & Buño, W. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.04.005 · Cited by 65 · see citing works
Artinian, J., & Lacaille, J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.11.012 · Cited by 61 · see citing works
Andrade‐Talavera, Y., Fisahn, A., & Moreno, A. R. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02027-w · Cited by 69 · see citing works
“Brain rhythms emerge from the entrainment of circuits established by direct synaptic contact between neurons and indirect feedforward and feedback connections giving rise to rhythmic electrical fl uctuations that can be measured extracellularly [4, 17, 43, 111 – 113].”
BackgroundInfluentialTransplanted interneurons improve memory precision after traumatic brain injury
Zhu, B., Eom, J., & Hunt, R. F. (2019) · Nature Communications · doi:10.1038/s41467-019-13170-w · Cited by 67 · see citing works
Data‐driven integration of hippocampal CA1 synaptic physiology in silico
Ecker, A., Romani, A., Sáray, S., Káli, S., Migliore, M., Falck, J. E., Lange, S., Mercer, A., Thomson, A. M., Muller, E. B., et al. (2020) · Hippocampus · doi:10.1002/hipo.23220 · Cited by 55 · see citing works
“framework, we identified and extrapolated organizing principles to predict missing knowledge for a repertoire of connection types, for example, the short-term dynamics and peak conductance of synaptic connections between inhibitory interneurons (Klausberger & Somogyi, 2008; Pelkey et al., 2017), which remain largely u…”
BackgroundMethodInfluentialSoh, H., Park, S., Ryan, K., Springer, K., Maheshwari, A., & Tzingounis, A. V. (2018) · eLife · doi:10.7554/elife.38617 · Cited by 59 · see citing works
“Previous work suggests that loss of KCNQ2/3 function in interneurons would likely elevate their excitability (Lawrence et al., 2006; Pelkey et al., 2017), which in turn would increase GABAergic inhibition and decrease network excitability.”
BackgroundInfluentialNeurophysiologic implications of neuronal nitric oxide synthase
Kourosh‐Arami, M., Hosseini, N., Mohsenzadegan, M., Komaki, A., & Joghataei, M. T. (2020) · Reviews in the Neurosciences · doi:10.1515/revneuro-2019-0111 · Cited by 63 · see citing works
The microtubule cytoskeleton at the synapse
Parato, J., & Bartolini, F. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.135850 · Cited by 60 · see citing works
Total Number and Ratio of GABAergic Neuron Types in the Mouse Lateral and Basal Amygdala
Vereczki, V., Müller, K., Krizsán, É., Máté, Z., Fekete, Z., Rovira-Esteban, L., Veres, J. M., Erdélyi, F., & Hájos, N. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2700-20.2021 · Cited by 60 · see citing works
Khan, A. R., Geiger, L., Wiborg, O., & Czéh, B. (2020) · Cells · doi:10.3390/cells9041026 · Cited by 62 · see citing works
“GABAergic interneurons of the hippocampus make up only 10–20% of the total neuronal population [71], still their remarkable anatomical and physiological diversity allows them to regulate virtually all aspects of cellular and neural circuit function [72,73].”
BackgroundProcedures for Culturing and Genetically Manipulating Murine Hippocampal Postnatal Neurons
Moutin, E., Hemonnot-Girard, A.-L., Seube, V., Linck, N., Rassendren, F., Perroy, J., & Compan, V. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.00019 · Cited by 56 · see citing works
Veres, J. M., Andrási, T., Nagy-Pál, P., & Hájos, N. (2023) · eNeuro · doi:10.1523/eneuro.0070-23.2023 · Cited by 58 · see citing works
“Introduction Cortical structures comprise excitatory principal cells and various types of inhibitory neurons, including parvalbumin (PV) or cholecystokinin (CCK)-containing interneurons responsible for perisomatic inhibition, somatostatin (SST)-expressing dendritic inhibitory cells, neuronal nitric oxide synthase (nNO…”
BackgroundGlia: A major player in glutamate–GABA dysregulation‐mediated neurodegeneration
Sood, A., Kumari, P., Fernandes, V., Khatri, D. K., & Singh, S. B. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24977 · Cited by 60 · see citing works
“The specific stimulation of hippocampal CA1 GABAergic neurons by employing optogenetics has increased gamma and theta power nested oscillations (Pelkey et al., 2017) and decreased the protein expression of glial activation markers (Jiang et al., 2017), suggesting that GABA suppresses pro-…”
BackgroundGating of hippocampal rhythms and memory by synaptic plasticity in inhibitory interneurons
He, X., Li, J., Zhou, G., Yang, J., McKenzie, S., Li, Y., Li, W., Yu, J., Wang, Y., Qu, J., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.01.014 · Cited by 56 · see citing works
Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells
Chittajallu, R., Auville, K., Mahadevan, V., Lai, M., Hunt, S., Calvigioni, D., Pelkey, K. A., Zaghloul, K. A., & McBain, C. J. (2020) · eLife · doi:10.7554/elife.57571 · Cited by 51 · see citing works
“At the cellular level, dendritic inhibition exerts a strong influence on excitability and electrogenesis in distal pyramidal cell subdomains(Kepecs & Fishell, 2014; Pelkey et al., 2017).”
BackgroundInfluentialSelf-citationFernandez, F. R., Via, G., Canavier, C. C., & White, J. A. (2022) · eNeuro · doi:10.1523/eneuro.0441-21.2022 · Cited by 51 · see citing works
Inhibitory control of sharp-wave ripple duration during learning in hippocampal recurrent networks
Vancura, B., Geiller, T. C., Grosmark, A., Zhao, V. M., & Losonczy, A. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01306-7 · Cited by 54 · see citing works
Somatostatin Interneurons Promote Neuronal Synchrony in the Neonatal Hippocampus
Floßmann, T., Kaas, T., Rahmati, V., Kiebel, S. J., Witte, O. W., Holthoff, K., & Kirmse, K. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.02.061 · Cited by 47 · see citing works
Medial septal GABAergic neurons reduce seizure duration upon optogenetic closed-loop stimulation
Hristova, K., Martinez‐Gonzalez, C., Watson, T. C., Codadu, N. K., Hashemi, K. S., Kind, P. C., Nolan, M. F., & Gonzalez‐Sulser, A. (2021) · Brain · doi:10.1093/brain/awab042 · Cited by 51 · see citing works
Camp, C. R., & Yuan, H. (2019) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2019.12.007 · Cited by 53 · see citing works
Beckmann, D., Feldmann, M., Shchyglo, O., & Manahan‐Vaughan, D. (2020) · Cerebral Cortex · doi:10.1093/cercor/bhaa061 · Cited by 52 · see citing works
Shao, F., Fang, J., Wang, S., Qiu, M., Xi, D., Jin, X., Liu, J., Shao, X., Shen, Z., Liang, Y., et al. (2021) · Molecular Brain · doi:10.1186/s13041-021-00849-9 · Cited by 53 · see citing works
“This is consistent with a previous study about on GABAergic neuron function in the brain [57].”
ResultEinenkel, A., & Salameh, A. (2023) · Journal of Neuroscience Research · doi:10.1002/jnr.25276 · Cited by 56 · see citing works
“Another interesting starting point could be found in the involvement of interneurons, which account for approximately 10%–15% of the total neuronal cell population (Pelkey et al., 2017 ).”
BackgroundInfluentialStep by step: cells with multiple functions in cortical circuit assembly
Cossart, R., & Garel, S. (2022) · Nature reviews. Neuroscience · doi:10.1038/s41583-022-00585-6 · Cited by 48 · see citing works
RNAseq analysis of hippocampal microglia after kainic acid-induced seizures
Bosco, D. B., Zheng, J., Xu, Z., Peng, J., Eyo, U. B., Tang, K., Yan, C., Huang, J., Feng, L., Wu, G., et al. (2018) · Molecular Brain · doi:10.1186/s13041-018-0376-5 · Cited by 54 · see citing works
“Since the hippocampus has a significant population of GABAergic interneurons, particularly in the CA1 and CA3 regions, it may be of interest to determine to what extent this crosstalk exists and whether or not blockage of this communication could alleviate seizure symptoms [67].”
BackgroundGeneration of Sharp Wave-Ripple Events by Disinhibition
Evangelista, R., Cano, G., Cooper, C., Schmitz, D., Maier, N., & Kempter, R. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2174-19.2020 · Cited by 46 · see citing works
“…between principal cells and interneurons, as well as connectivities among interneurons, are distributed in the range 0%-90%: for hippocampus (Böhm et al., 2015; Kohus et al., 2016; Pelkey et al., 2017; Booker and Vida, 2018); for neocortex (Kwan and Dan, 2012; Walker et al., 2016; Riedemann, 2019).”
BackgroundResultSelective vulnerability of hippocampal interneurons to graded traumatic brain injury
Frankowski, J. C., Kim, Y. J., & Hunt, R. F. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.022 · Cited by 49 · see citing works
“However, interneurons have classically been distinguished based on their unique neurochemical signatures (Freund and Buzsáki, 1996; Pelkey et al., 2017).”
BackgroundSpecificity of Primate Amygdalar Pathways to Hippocampus
Wang, J., & Barbas, H. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1267-18.2018 · Cited by 48 · see citing works
“The morphologic evidence suggests that these dendrites belong to inhibitory neurons that express CB or somatostatin, as described for rats and mice (for review, see Klausberger, 2009; Pelkey et al., 2017).”
BackgroundThalamic inhibitory circuits and network activity development
Murata, Y., & Colonnese, M. T. (2018) · Brain Research · doi:10.1016/j.brainres.2018.10.024 · Cited by 49 · see citing works
Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model
Rice, H. C., Marcassa, G., Chrysidou, I., Horré, K., Young‐Pearse, T. L., Müller, U., Saito, T., Saido, T. C., Vassar, R. J., de Wit, J., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0356-y · Cited by 51 · see citing works
Murata, K., Kinoshita, T., Ishikawa, T., Kuroda, K., Hoshi, M. M., & Fukazawa, Y. (2020) · The Journal of Comparative Neurology · doi:10.1002/cne.24924 · Cited by 52 · see citing works
“GABAergic interneurons in the hippocampus and neocortex have numerous anatomical, physiological, and biochemical diversity (Pelkey et al., 2017).”
BackgroundPai, E. L.-L., Chen, J., Darbandi, S. F., Cho, F. S., Chen, J., Lindtner, S., Chu, J. S. F., Paz, J. T., Vogt, D. L., Paredes, M. F., et al. (2020) · eLife · doi:10.7554/elife.54903 · Cited by 43 · see citing works
“However, so far there are no clear single markers that are known to define developing or mature HINs from CINs (Pelkey et al., 2017).”
BackgroundParadoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons
Pelkey, K. A., Calvigioni, D., Fang, C., Vargish, G., Ekins, T., Auville, K., Wester, J. C., Lai, M., Mackenzie-Gray Scott, C., Yuan, X., et al. (2020) · eLife · doi:10.7554/elife.51996 · Cited by 46 · see citing works
Self-citationLuo, X. M., Guet-McCreight, A., Villette, V., Francavilla, R., Marino, B., Chamberland, S., Skinner, F. K., & Topolnik, L. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz334 · Cited by 50 · see citing works
“different computations carried out by principal cells (PCs) (Soltesz 2006; Klausberger and Somogyi 2008; Pelkey et al. 2017).”
MethodRegion and Cell Type Distribution of TCF4 in the Postnatal Mouse Brain
Kim, H., Berens, N., Ochandarena, N. E., & Philpot, B. D. (2020) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2020.00042 · Cited by 46 · see citing works
Plasticity in the Hippocampus, Neurogenesis and Drugs of Abuse
Avchalumov, Y., & Mandyam, C. D. (2021) · Brain Sciences · doi:10.3390/brainsci11030404 · Cited by 49 · see citing works
“We limit our discussion to the excitatory neurons in this review, and direct the readers to other publications for more information on the inhibitory neurons [52,53].”
BackgroundStructured inhibitory activity dynamics in new virtual environments
Arriaga, M. A., & Han, E. B. (2019) · eLife · doi:10.7554/elife.47611 · Cited by 48 · see citing works
Reorganization of CA1 dendritic dynamics by hippocampal sharp-wave ripples during learning
Rolotti, S. V., Blockus, H., Sparks, F. T., Priestley, J. B., & Losonczy, A. (2022) · Neuron · doi:10.1016/j.neuron.2021.12.017 · Cited by 50 · see citing works
Young, W. S., & Song, J. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00040 · Cited by 42 · see citing works
Winterer, J., Lukacsovich, D., Que, L., Sartori, A. M., Luo, W., & Földy, C. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14549 · Cited by 40 · see citing works
“In addition, all cells displayed pronounced ‘sag’ potential upon hyperpolarizing current injections, spike frequency adaptation and a maximum firing frequency of <100 Hz that distinguishes them from prototypical fast‐spiking interneurons (Booker & Vida, 2018; Pelkey et al., 2017).”
BackgroundResultInfluentialPhenotypic variation within and across transcriptomic cell types in mouse motor cortex
(2020) · doi:10.1101/2020.02.03.929158 · Cited by 397 · see citing works
“, 2018), this suggests that although all deep NGCs belong to the Lamp5 family, some are CGE- and some are MGE-derived [as is the case in hippocampus (Tricoire et al., 2010; Pelkey et al., 2017; Harris et al., 2018)], resolving an open question in the field (Huang and Paul, 2019).”
Background
- Authors
- Pelkey, K. A., Chittajallu, R., Craig, M. T., Tricoire, L., Wester, J. C., & McBain, C. J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 2017-10-01
- Volume
- 97
- Issue
- 4
- Pages
- 1619-1747
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- PMC
- PMC6151493
- OpenAlex
- W2759536331
- Semantic Scholar
- 57ac72477def0a717ede2bdc3cea815e1654b0d2
- Cited by
- 889
- References
- 1,303
- Citations by year
- 2026: 76 · 2025: 124 · 2024: 119 · 2023: 116 · 2022: 109 · 2021: 133 · 2020: 110 · 2019: 68 · 2018: 32 · 2017: 1
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Physiological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Open Research Exeter (University of Exeter) (acceptedVersion)
- Figshare (submittedVersion)
- Funders
- HHS | NIH | National Institute of Child Health and Human Development (NICHD) (Z1A-HD001205-24)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- hippocampus, GABAergic interneurons, inhibitory interneurons, interneuron subtypes, interneuron development, voltage-gated ion channels, ligand-gated ion channels, network oscillations, treatment options
- MeSH terms
- Animals, Central Nervous System Diseases, gamma-Aminobutyric Acid, Hippocampus, Humans, Interneurons, Nerve Net, Neural Inhibition, Synaptic Transmission, Receptors, GABA, GABAergic Neurons
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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