Principles of NMDA receptor co-agonism at cortical fast-spiking GABAergic interneurons in the adolescent prefrontal cortex

N-methyl-D-aspartate receptors (NMDARs) populate fast-spiking (FS)-parvalbumin-positive (PV+) GABAergic interneurons (INs), where they play a critical role in shaping circuit motifs and memory. However, it is largely unknown whether and how NMDARs at FS-PV+-INs are gated by their co-agonists and the functional relevance of such modulations for their synaptic coupling with excitatory neurons. Here, we report that FS-PV+-INs in the adolescent mouse prefrontal cortex, an area central to complex cognitive operation exhibit functional GluN2B/D containing NMDARs. These receptors contribute to the excitatory drive of FS-PV+-INs and to the feedforward inhibition, controlling short-term and long-term synaptic plasticity. While the identity of the co-agonist controlling GABAergic tone is tuned by the synaptic activity regime from D-serine to glycine, we reveal that it remains largely unchanged at the excitatory synapse with D-serine being the sole co-agonist gating NMDARs. Lastly, we show that D-serine-deficient mice, a model of NMDAR hypofunction show selective attenuation of PV+-INs excitation together with selective loss of temporal summation and long-term plasticity at the excitatory synapse. Our study reveals the segregation of pools of NMDARs at the soma and dendrites that are differently sensitive to D-serine or glycine, the existence of distinct modes of activity-dependent regulation of these NMDARs by their co-agonists at this major type of GABAergic INs, and hence the rules governing cortical inhibition by FS-PV+-INs during a critical period of late postnatal development.