The NMDA receptor subunit GluN2D is a potential target for rapid antidepressant action
Abstract
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.
Article Details
Authors (44)
Stefan Vestring
Maxime Veleanu
Marina Conde Perez
Louise E. Schuberth
Martin Bronnec
Anna Li
Nuffield Department of Clinical Neurosciences, University of Oxford
Lovis M. Würz
Fatih Erdogdu
Julia Stocker
Johanna Moos
David Weigel
Alice Theiß
Elisabeth Wendler
Lotta M. Borger
Sabine Voita
Franziska Heynicke
Jakob Brandl
Fabian Hummel
Clotilde Vivet
Dorothea Jocher
Pauline Loewe
Simon Barmann
Lea Smoltczyk
Stella Zimmermann
Prejwal Prabhakaran
Granita Lokaj
David H. Sarrazin
Guillermo Suarez
Judith Bernhardt
Catherine du Vinage
Elisa Grießbach
Julia Lais
Nicole Gensch
Magdalena Wojtas
Institute of Biomedical Engineering, University of Toronto
Shira Knafo
Jule Wendel
Jan Warneke
Jean-Paul Grohe
Stefan Günther
Aurélien F. A. Moumbock
Katharina Domschke
Tsvetan Serchov
Josef Bischofberger
Claus Normann