The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action
S. Vestring, M. Veleanu, Marina Conde Perez, Louise Schuberth, Martin Bronnec, Anna Li, Lovis M. Würz, Fatih Erdogdu, Jule E. Stocker, Johanna Moos, David C. Weigel, A. Theiss, Elisabeth Wendler, Lotta M. Borger, Sabine Voita, Franziska Heynicke, Jakob Brandl, F. Hummel, Clotilde Vivet, Dorothea Jocher, P. Loewe, Simon Barmann, Lea Smoltczyk, S. Zimmermann, Prejwal Prabhakaran, Granita Lokaj, David H. Sarrazin, Guillermo Suarez, Judith Bernhardt, Catherine Du Vinage, Elisa Grießbach, Julia Lais, Nicole Gensch, Magdalena Wojtas, S. Knafo, J. Wendel, J. Warneke, Jean-Paul Grohe, S. Guenther, Aurélien F. A. Moumbock, K. Domschke, T. Serchov, Josef Bischofberger, Claus Normann
Nature Communications November 26, 2025 DOI: 10.1038/s41467-025-66774-w (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice, including a mouse model of depression; hippocampal slices |
| Interventions | Ketamine NAB-14 Grin2d-siRNA chemogenetic approaches |
| Key findings | The authors report that ketamine preferentially targets GluN2D-containing NMDA receptors on interneurons, and that selective GluN2D antagonism inhibits interneuron NMDA currents, restores stress-impaired excitation-inhibition balance and plasticity, and mimics ketamine's rapid antidepressant-like effects in mice with fewer side effects. They propose GluN2D as a specific target for novel antidepressant therapy. |
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. Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.