GLUN2D‑CONTAINING NMDA RECEPTORS IN HIPPOCAMPAL INTERNEURONS REGULATE INHIBITORY FEEDBACK CIRCUITS AND RESTORE PLASTICITY IN DEPRESSION MODELS

Major depression is associated with disrupted excitation–inhibition (E/I) balance and impaired synaptic plasticity in cortical and hippocampal circuits We investigated the role of NMDA receptors containing the GluN2D subunit in hippocampal microcircuits using ex vivo electrophysiology, subtype‑selective pharmacology (NAB‑14), siRNA‑mediated knockdown, and chemogenetic tools in acute mouse brain slices, alongside behavioral assays in a stress‑induced depression model. GluN2D antagonism, via NAB‑14 and ketamine, preferentially reduced NMDAR‑mediated currents in interneurons relative to pyramidal cells, reflecting the enrichment of GluN2D subunits in somatostatin‑ and parvalbumin‑expressing interneurons. This selective inhibition differentially modulated feedback and feed‑forward inhibitory loops impacting dendritic and somatic inhibition of CA1 pyramidal cells. Knockdown of GluN2D reduced interneuron NMDAR currents, and chemogenetic disruption of GluN2D‑expressing interneurons altered inhibitory control over pyramidal activity. In a mouse depression model, GluN2D inhibition normalized E/I ratios, reversed deficits in long‑term potentiation, and restored synaptic AMPA‑receptor expression patterns. These findings indicate that GluN2D‑containing NMDARs on specific interneuron subclasses critically regulate inhibitory feedback circuits and can rebalance hippocampal network activity and plasticity, identifying GluN2D as a mechanistic entry point for rapid modulation of depression‑relevant circuitry.