How GluN2D-targeting drugs and ketamine influence inhibitory signals, long-term brain strengthening, and motivation

GluN2D-NMDARs at presynaptic terminals of hippocampal parvalbumin-interneurons are activated by changes in basal glutamate to control GABA release.

• GABAergic interneurons play a critical role in balancing brain activity by suppressing excessive signaling.
• The specific composition of NMDAR subunits in interneurons is largely unknown, despite their importance.
• GluN2D-NMDARs contain presynaptic targeting information within their intracellular C-terminal.
• Inhibition of GABA release by certain modulators is absent in mice lacking GluN2D in parvalbumin-interneurons.
• The selective inhibitor NAB14 mimics ketamine's effects on long-term potentiation and reward motivation in a depression model without its negative side effects.

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