ArticleNature communications2025
The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action.
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Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10citing papers in PubMed
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Who cites it
10 citing papers in PubMed.
- GluN2D NMDA Receptors: Bridging Physiology and Pathology.Biological psychiatry · 2026Review
- Smooth emotional response: amygdalar neurovascular coupling drives stress encoding.Cell research · 2026Article
- The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response.Nature communications · 2026Article
- [(Es)ketamine: practice update].Der Nervenarzt · 2026Review
- Bidirectional control of vesicular GABA release, LTP, and amotivation by GluN2D-selective allosteric modulators and ketamine.Cell reports · 2026Article
- From synapse to strategy: a bibliometric map of ionotropic glutamate receptors in depression.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Novel approaches in depression treatment: from rapid-acting antidepressants to personalized interventions.Molecular psychiatry · 2026Review
- A depression-like phenotype is associated with discrete defects in the primary hippocampal circuit.Translational psychiatry · 2026Article
- Increase of the AMPA-evoked response of pyramidal neurons in the rat medial prefrontal cortex following acute administration of ketamine and S-ketamine, but not R-ketamine.The international journal of neuropsychopharmacology · 2026Article
- The Connectomic Glutamate Framework for Depression: Bridging Molecular Plasticity and Network Reorganization.Brain sciences · 2025Review
Corrections and comments
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Authors and funding
44 authors.
Stefan VestringDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0001-9150-8712
Maxime VeleanuDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0001-6760-3488
Marina Conde PerezDepartment of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Louise E SchuberthDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0005-1338-7261
Martin BronnecDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Anna LiDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Lovis M WürzDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Fatih ErdogduDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Julia StockerDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Johanna MoosDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
David WeigelDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Alice TheißDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Elisabeth WendlerDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Lotta M BorgerDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0006-0747-4163
Sabine VoitaDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Franziska HeynickeDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0003-4089-1103
Jakob BrandlDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0005-8212-1758
Fabian HummelDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0008-9077-9762
Clotilde VivetDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Dorothea JocherDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0005-7175-2079
Pauline LoeweDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Simon BarmannDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Lea SmoltczykDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Stella ZimmermannDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Prejwal PrabhakaranDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0007-3845-535X
Granita LokajDepartment of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
David H SarrazinCentre National de la Recherche Scientifique (CNRS) UPR3212, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives (INCI), Strasbourg, France.ORCID http://orcid.org/0000-0003-1326-3232
Guillermo SuarezDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0009-0005-6219-0174
Judith BernhardtDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Catherine du VinageDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Elisa GrießbachDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Julia LaisDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Nicole GenschCore Facility Signaling Factory, Centre for Biological Signaling Studies (BIOSS), University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0003-4578-6409
Magdalena WojtasDepartment of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (EHU), Leioa, Spain.
Shira KnafoDepartment of Cell Biology and Histology, Faculty of Medicine and Nursing, University of the Basque Country (EHU), Leioa, Spain.ORCID http://orcid.org/0000-0002-4478-7584
Jule WendelDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Jan WarnekeDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Jean-Paul GroheDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Stefan GüntherInstitute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0003-3744-189X
Aurélien F A MoumbockInstitute of Pharmaceutical Sciences, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0002-6034-2016
Katharina DomschkeDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0002-2550-9132
Tsvetan SerchovDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.ORCID http://orcid.org/0000-0002-2234-2875
Josef BischofbergerDepartment of Biomedicine, University of Basel, Basel, Switzerland.ORCID http://orcid.org/0000-0002-4006-1663
Claus NormannDepartment of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. claus.normann@uniklinik-freiburg.de.ORCID http://orcid.org/0000-0001-5693-8936
Funding
Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Federal Ministry for Education, Science, Research and Technology) GO-Bio INNOVADE 16LW0223Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Federal Ministry for Education, Science, Research and Technology) GO-Bio INNOVADE 16LW0455Centre National de la Recherche Scientifique (National Center for Scientific Research) CNRS UPR3212Deutsche Forschungsgemeinschaft (German Research Foundation) SE266/2-1Fondation pour la Recherche Médicale (Foundation for Medical Research in France) AJE201912009450Université de Strasbourg (University of Strasbourg) USIAS 2020-035
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.
Indexed as
Antidepressive AgentsDepressionKetamineReceptors, N-Methyl-D-AspartateAnimalsDisease Models, AnimalHippocampusInterneuronsMaleMiceMice, Inbred C57BLNeuronal PlasticityPyramidal CellsAntidepressive AgentsKetamineNR2D NMDA receptorReceptors, N-Methyl-D-Aspartate
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