Bidirectional control of vesicular GABA release, LTP, and amotivation by GluN2D-selective allosteric modulators and...

GABAergic inhibitory interneurons balance brain activity by suppressing excessive excitatory signaling and shaping network oscillations. Despite this critical function, our understanding of how neural circuits regulate GABAergic systems remains limited. Although N-methyl-D-aspartate receptor (NMDAR) functionality is defined by the GluN2A-D subunits, the interneuron NMDAR subunit composition remains unknown. Here, we show that GluN2D-NMDARs reside at presynaptic terminals of hippocampal parvalbumin-interneurons, and that the GluN2D intracellular C-terminal contains presynaptic targeting information. GluN2D-NMDARs are activated by changes in basal glutamate to bidirectionally control GABA release. Importantly, inhibition of GABA release by GluN2C/D modulators and subanesthetic ketamine is absent in mice lacking GluN2D in parvalbumin-interneurons, suggesting that GluN2D-dependent presynaptic regulation of GABA release may underlie some of ketamine's effects. The GluN2C/D-selective inhibitor NAB14 recapitulates durable ketamine-induced enhancement of long-term potentiation (LTP) and recovery of reward motivation in a behavioral model of depression without ketamine's undesirable effects, suggesting that GluN2D-NMDARs could be a therapeutically relevant target.