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Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus

Significance NMDA receptors (NMDARs) support patterning and activity of synapses throughout life and are central to many brain disorders. The NMDAR activation requires the concomitant binding of glutamate and a coagonist glycine or d-serine. To date, whether a preference for one coagonist at specific connections occurs remains unsolved. Here, we sought to determine when and where d-serine and glycine enter into play at hippocampal synapses. We demonstrate that the identity of the NMDAR coagonist is synapse specific and developmentally regulated. Remarkably, this segregation coincides with the subunit composition of postsynaptic NMDARs and the maturation of the tripartite synapse. These results point out the importance of the spatial and temporal switch in coagonist identity for therapeutic interventions aimed at treating deficits in NMDAR activity. NMDA receptors (NMDARs) require the coagonists d-serine or glycine for their activation, but whether the identity of the coagonist could be synapse specific and developmentally regulated remains elusive. We therefore investigated the contribution of d-serine and glycine by recording NMDAR-mediated responses at hippocampal Schaffer collaterals (SC)–CA1 and medial perforant path–dentate gyrus (mPP–DG) synapses in juvenile and adult rats. Selective depletion of endogenous coagonists with enzymatic scavengers as well as pharmacological inhibition of endogenous d-amino acid oxidase activity revealed that d-serine is the preferred coagonist at SC–CA1 mature synapses, whereas, unexpectedly, glycine is mainly involved at mPP–DG synapses. Nevertheless, both coagonist functions are driven by the levels of synaptic activity as inferred by recording long-term potentiation generated at both connections. This regional compartmentalization in the coagonist identity is associated to different GluN1/GluN2A to GluN1/GluN2B subunit composition of synaptic NMDARs. During postnatal development, the replacement of GluN2B- by GluN2A-containing NMDARs at SC–CA1 synapses parallels a change in the identity of the coagonist from glycine to d-serine. In contrast, NMDARs subunit composition at mPP–DG synapses is not altered and glycine remains the main coagonist throughout postnatal development. Altogether, our observations disclose an unprecedented relationship in the identity of the coagonist not only with the GluN2 subunit composition at synaptic NMDARs but also with astrocyte activity in the developing and mature hippocampus that reconciles the complementary functions of d-serine and glycine in modulating NMDARs during the maturation of tripartite glutamatergic synapses.