The NMDA receptor subunit GluN2D is a target for rapid antidepressant action

Abstract Ketamine is the first glutamatergic agent in clinical use for major depression. The underlying mechanism and primary target of ketamine are unknown; further research is urgently needed to develop more specific interventions with fewer side effects and better treatment outcomes for severely affected patients. Ketamine is a noncompetitive antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, a heterotetramer composed of two GluN1 and two GluN2 subunits. Here, we show that ketamine preferentially targets GluN2D-containing NMDA receptors on interneurons, and that selective GluN2D antagonism alone is sufficient to produce rapid antidepressant effects. We used ketamine, selective GluN2D inhibitors, GRIN2D-siRNA and chemogenetic approaches in hippocampal brain slices and in vivo in mice. We found that GluN2D antagonism inhibited NMDAR currents in interneurons but not in pyramidal cells. GluN2D-mediated recruitment of GABAergic interneurons powerfully controls feedback and feed-forward inhibitory circuits to moderate hippocampal network activity and synaptic plasticity. In a mouse model of depression, GluN2D inhibition recovered synaptic excitation-inhibition balance, reversed long-term potentiation deficits and restored synaptic and AMPAR density toward a naïve state. GluN2D antagonism could fully mimic the cellular and behavioral antidepressant actions of ketamine with fewer side effects in terms of motor coordination and anxiety. These findings identify novel and a highly specific target for drug treatment of major depression.