GluN2D-Containing N-methyl-d-Aspartate Receptors Mediate Synaptic Transmission in Hippocampal Interneurons and Regulate Interneuron Activity
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N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d-/- mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (+)-CIQ potentiation and was not accelerated in slices from Grin2d-/- mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing.
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Grin2d is found in hippocampal interneurons and enhances their activity due to its involvement in synaptic transmission.
“Furthermore, Grin2d has been found in hippocampal interneurons and enhances their activity due to its involvement in synaptic transmission66.”
From Elimination of the four extracellular matrix molecules tenascin-C, tenascin-R, brevican and neurocan alters the ratio of excitatory and inhibitory synapses (2019) · cites this paper as [66]
Ketamine has higher affinity for GluN2D NMDAR subunits, which are highly expressed in forebrain inhibitory interneurons.
“In addition, ketamine is reported to have higher affinity for GluN2D NMDAR subunits 40, 41, which are highly expressed in forebrain inhibitory interneurons 42, 43.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [43]
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NMDA Receptors in Neurodevelopmental Disorders: Pathophysiology and Disease Models
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A Role for Prefrontal Cortical NMDA Receptors in Murine Alcohol-Heightened Aggression
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Ketamine for post-traumatic stress disorders and it's possible therapeutic mechanism
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NMDA receptor GluN2D subunit participates to levodopa-induced dyskinesia pathophysiology
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NMDA receptor function in inhibitory neurons
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PTC-174, a positive allosteric modulator of NMDA receptors containing GluN2C or GluN2D subunits
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Self-citationTargeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder
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NMDAR PAMs: Multiple Chemotypes for Multiple Binding Sites
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The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action
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Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia
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Synaptic dysregulation in a mouse model of GRIN2D developmental and epileptic encephalopathy
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Self-citationPromises and Pitfalls of NMDA Receptor Antagonists in Treating Violent Aggression
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Inhibition of GluN2B-containing N -methyl- D- aspartate receptors by radiprodil
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GluN2D expression is regulated by restraint stress and supports active stress coping bouts
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Self-citationExtending the Small Molecule Similarity Principle to All Levels of BiologyPreprint
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The Sustained Antidepressant Effects of Ketamine Are Independent of the Lateral Habenula
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Selective Cell-Surface Expression of Triheteromeric NMDA Receptors
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Self-citationA Plate-Based Assay for the Measurement of Endogenous Monoamine Release in Acute Brain Slices
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Enhancement of hippocampal interneuron excitability by NMDA receptor positive allosteric modulation
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21st century excitatory amino acid research: A Q & A with Jeff Watkins and Dick Evans
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- Authors
- Perszyk, R. E., DiRaddo, J. O., Strong, K. L., Low, C.-M., Ogden, K. K., Khatri, A., Vargish, G. A., Pelkey, K. A., Tricoire, L., Liotta, D. C., Smith, Y., McBain, C. J., & Traynelis, S. F.
- Affiliations
- National Institutes of Health (US)
- ORCID
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 90
- Issue
- 6
- Pages
- 689-702
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC5118640
- OpenAlex
- W2548997185
- Cited by
- 116
- References
- 59
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 9 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 15 · 2019: 13 · 2018: 9 · 2017: 8 · 2016: 1
- FWCI
- 5.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- University of Florida
- National Institutes of Health (P51OD011132)
- National Institute of General Medical Sciences (T32GM008602)
- National Institute of Neurological Disorders and Stroke (R01NS065371, R01NS036654)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- GluN2D, NMDA receptor, hippocampal interneurons, synaptic transmission, positive allosteric modulation, miniature excitatory postsynaptic currents, spontaneous inhibitory postsynaptic currents, CA1, glutamatergic synapses
- MeSH terms
- Allosteric Regulation, Animals, Hippocampus, Interneurons, Isoquinolines, Mice, Inbred C57BL, Synaptic Transmission, RNA, Messenger, Stereoisomerism, Time Factors, Xenopus laevis, Ion Channel Gating, Receptors, N-Methyl-D-Aspartate, Excitatory Postsynaptic Potentials, Rats, CA1 Region, Hippocampal, Real-Time Polymerase Chain Reaction
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