The Regulation of NMDA Receptors at GABAergic Interneurons During Postnatal Development

Abstract

Brain development is marked by periods of enhanced brain plasticity, known as critical periods. The termination of critical periods requires the maturation of parvalbumin-positive interneurons (PV+ INs). Several studies have linked the disruption of N-methyl D-aspartate receptors (NMDARs) in PV+ INs during postnatal development to the pathophysiology of schizophrenia and autism spectrum disorders. Canonical NMDA receptors are hetero tetramers with two GluN1 and two GluN2 subunits, which together form an ion channel. GluN2 subunits can be of four classes- GluN2A/B/C/D. NMDAR activation requires the simultaneous binding of the excitatory neurotransmitter glutamate, and a co-agonist, which can be glycine or D-serine. Recent studies by our lab have found that in adult mice, D-serine but not glycine is critical for maintaining the activity of NMDARs at PV+ INs in the late adolescent-young adult prefrontal cortex (PFC), and that loss of D-serine functions leads to the synaptic deficits observed in neuropsychiatric disorders such as schizophrenia. However, it is not known if the identity of the NMDAR co-agonist in these cells is developmentally regulated. Through this study, I aim to test the functions of D-serine and glycine as NMDAR co-agonists throughout postnatal development using the transgenic PV+-tdTomato mice where PV+ INs are readily identifiable. Using selective enzymatic scavengers to block the function of either D-serine or glycine, I reveal that D-serine but not glycine gates NMDARs at the PFC PV+ INs at juvenile synapses (11-17 day old mice). Strikingly, I also show that bath application of D-serine inhibits NMDA-EPSCs at PV+ in neonates (11-17 days-old) while it does increase the synaptic responses in mature synapses (45-70 days old). Finally, I test the hypothesis for a change in the composition of NMDARs subunits INs during development. Overall, this study helps in understanding the relative in PFC PV+ contribution of D-serine and glycine in the regulation of specific NMDARs at PV+ INs during postnatal development.