The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action
Open accessPublished version of a preprint
Abstract
Ketamine is the first glutamatergic agent in clinical use for major depression, but its primary target remains unclear. Further research is needed to develop more specific interventions with fewer side effects. Ketamine is a noncompetitive antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Here, we show that ketamine preferentially targets GluN2D-containing NMDA receptors on interneurons, and that selective GluN2D antagonism is sufficient to produce rapid antidepressant-like effects. We use ketamine, the selective GluN2C/D inhibitor NAB-14, Grin2d -siRNA and chemogenetic approaches in hippocampal slices and in vivo mice. We find that GluN2D antagonism inhibits NMDAR currents in interneurons but not pyramidal cells, and that GluN2D-mediated recruitment of GABAergic interneurons controls inhibitory circuits regulating hippocampal activity and plasticity. In a mouse model of depression, GluN2D inhibition recovers excitation-inhibition balance, restores plasticity, and mimics antidepressant-like actions of ketamine with fewer side effects. These findings identify GluN2D as a highly specific target for novel antidepressant therapy.
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References 122 · Cited by 13
- Authors
- Vestring, S., Veleanu, M., Perez, M. C., Schuberth, L. E., Bronnec, M., Li, A., Würz, L. M., Erdogdu, F., Stocker, J., Moos, J., Weigel, D., Theiß, A., Wendler, E., Borger, L. M., Voita, S., Heynicke, F., Brandl, J., Hummel, F., Vivet, C., Jocher, D., Loewe, P., Barmann, S., Smoltczyk, L., Zimmermann, S., Prabhakaran, P., Lokaj, G., Sarrazin, D. H., Suarez, G., Bernhardt, J., du Vinage, C., Grießbach, E., Lais, J., Gensch, N., Wojtas, M., Knafo, S., Wendel, J., Warneke, J., Grohe, J.-P., Günther, S., Moumbock, A. F. A., Domschke, K., Serchov, T., Bischofberger, J., & Normann, C.
- Affiliations
- University of Freiburg (DE)
- Centre National de la Recherche Scientifique (FR)
- University of the Basque Country (ES)
- Ikerbasque (ES)
- University of Basel (CH)
- Corresponding author
- Normann, Claus
- ORCID
- Vestring, Stefan
- Veleanu, Maxime
- Schuberth, Louise E.
- Borger, Lotta M.
- Heynicke, Franziska
- Brandl, Jakob
- Hummel, Fabian
- Jocher, Dorothea
- Prabhakaran, Prejwal
- Sarrazin, David H.
- Suarez, Guillermo
- Gensch, Nicole
- Wojtas, Magdalena
- Knafo, Shira
- Günther, Stefan
- Moumbock, Aurélien F. A.
- Domschke, Katharina
- Serchov, Tsvetan
- Bischofberger, Josef
- Normann, Claus
- Venue
- Nature Communications
- Published
- 2025-11-26
- Volume
- 16
- Issue
- 1
- Pages
- 10613-10613
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12660997
- OpenAlex
- W4416758783
- Cited by
- 13
- References
- 122
- Citations by year
- 2026: 12 · 2025: 1
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- HAL (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SE266/2-1)
- Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (GO-Bio INNOVADE 16LW0223, GO-Bio INNOVADE 16LW0455)
- Fondation pour la Recherche Médicale (AJE201912009450)
- Université de Strasbourg (USIAS 2020-035)
- Centre National de la Recherche Scientifique (CNRS UPR3212)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- GluN2D, NMDA receptor, ketamine, major depressive disorder, interneurons, GABAergic inhibition, excitation-inhibition balance, hippocampus, synaptic plasticity, GRIN2D, chemogenetics, siRNA
- MeSH terms
- Animals, Antidepressive Agents, Depression, Disease Models, Animal, Hippocampus, Interneurons, Ketamine, Male, Mice, Inbred C57BL, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate, Pyramidal Cells, Mice
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