K+ Channels at the Axon Initial Segment Dampen Near-Threshold Excitability of Neocortical Fast-Spiking GABAergic Interneurons
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Fast-spiking cells (FS cells) are a prominent subtype of neocortical GABAergic interneurons with important functional roles. Multiple FS cell properties are coordinated for rapid response. Here, we describe an FS cell feature that serves to gate the powerful inhibition produced by FS cell activity. We show that FS cells in layer 2/3 barrel cortex possess a dampening mechanism mediated by Kv1.1-containing potassium channels localized to the axon initial segment. These channels powerfully regulate action potential threshold and allow FS cells to respond preferentially to large inputs that are fast enough to "outrun" Kv1 activation. In addition, Kv1.1 channel blockade converts the delay-type discharge pattern of FS cells to one of continuous fast spiking without influencing the high-frequency firing that defines FS cells. Thus, Kv1 channels provide a key counterbalance to the established rapid-response characteristics of FS cells, regulating excitability through a unique combination of electrophysiological properties and discrete subcellular localization.
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One set of co-expressed genes encoded proteins that enable fast and persistent action potentials, including Kcnc1-3 (Kv3.1), Kcna1 (Kv1.1) and Scn8a (Nav1.6) channels.
“One set of co-expressed genes encoded proteins that enable fast and persistent action potentials, including the Kcnc1–3 (Kv3.1), Kcna1 (Kv1.1) and Scn8a (Nav1.6) channels”
From Molecular diversity and specializations among the cells of the adult mouse brain (2018) · cites this paper as Goldberg et al., 2008
Kv1.1 is critical for delayed firing in PV+ basket cells.
“Since this channel is critical for delayed firing in these cells (Goldberg et al., 2008), this mechanism allows PV+ basket cells to reversibly adapt to changing levels of activity by dynamically tuning their excitability (Figure 7B).”
From Development and Functional Diversification of Cortical Interneurons (2018) · cites this paper as Goldberg et al., 2008
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.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
Both 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.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
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.
“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).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
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.
“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).”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
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.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
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.
“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.”
From Hippocampal GABAergic Inhibitory Interneurons (2017) · cites this paper as [415]
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- Authors
- Goldberg, E. M., Clark, B. D., Zagha, E., Nahmani, M., Erisir, A., & Rudy, B.
- Affiliations
- New York University (US)
- NYU Langone Health (US)
- Corresponding author
- Rudy, Bernardo
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 58
- Issue
- 3
- Pages
- 387-400
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2730466
- OpenAlex
- W2042186471
- Cited by
- 271
- References
- 5
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 25 · 2023: 15 · 2022: 15 · 2021: 16 · 2020: 7 · 2019: 9 · 2018: 12 · 2017: 14 · 2016: 15 · 2015: 18 · 2014: 19 · 2013: 22 · 2012: 11
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1939 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- University of Washington Tacoma Digital Commons (University of Washington Tacoma) (submittedVersion)
- Funders
- National Science Foundation
- Hearst Foundations
- National Institutes of Health (5r01ns030989-22)
- National Institute of Neurological Disorders and Stroke (NS-30989, R01-NS030989, F30 NS47882, R01NS045217, NS-045217, F30NS047882)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- fast-spiking interneurons, GABAergic interneurons, Kv1.1 potassium channel, axon initial segment, action potential threshold, neuronal excitability, barrel cortex, layer 2/3
- MeSH terms
- Action Potentials, Animals, Axons, Computer Simulation, gamma-Aminobutyric Acid, Interneurons, Mice, Transgenic, Microscopy, Electron, Organ Culture Techniques, Somatosensory Cortex, Patch-Clamp Techniques, Neocortex, Excitatory Postsynaptic Potentials, Green Fluorescent Proteins, Mice, Shaker Superfamily of Potassium Channels
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