Excitatory drive of cortical fast-spiking GABAergic interneurons is set by D-serine acting on NMDA receptors

Abstract N-methyl-D-aspartate receptors (NMDARs) populate GABAergic interneurons, where they play a critical role in shaping circuit motifs and memory. However, we are largely ignoring whether and how NMDARs at GABAergic interneurons are gated by signals released in their surrounding microenvironment. Here we explore the dynamics of the co-agonist site occupancy by D-serine and glycine at glutamatergic synapses onto parvalbumin positive GABAergic interneurons in the adolescent prefrontal cortex, an area central to complex cognitive operation. We discovered that D-serine but not glycine is required for maintaining the activity of NMDAR at the GABAergic interneurons and that the identity of the co-agonist is not determined by the synaptic regime. Our study extends the physiological implications of D-serine in brain physiopathology by uncovering its control of inhibitory synaptic networks through NMDARs.