| Abstract: | 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.The glutamate-gated N-methyl-d-aspartate receptors (NMDARs) play a critical role in structural and functional plasticity at synapses during postnatal brain development and in adulthood (1) and are therefore central to many cognitive functions such as learning and memory (2). Disturbances of their functions have been associated to a broad range of neurological and psychiatric disorders (3). NMDARs are heterotetramers typically composed of GluN1 and GluN2 subunits (3, 4), and the precise subunit composition determines NMDAR functional and trafficking properties (3, 4).NMDARs are unique among neurotransmitter receptors because their activation requires the binding of both glutamate and a coagonist initially thought to be glycine (5, 6). Nevertheless, subsequent studies have shown that d-serine synthesized by serine racemase (SR) (7) would be the preferred endogenous coagonist for synaptic NMDARs in many areas of the mature brain (8), raising controversies about “where, when, and how” glycine and d-serine might regulate NMDARs at synapses in the brain. This controversy is highlighted by the recent findings showing that d-serine and glycine both released by neurons come into play to regulate synaptic NMDAR-dependent functions at the hippocampal Schaffer collateral (SC)–CA1 synapses of adult brain (9), whereas others found no evidence for a function of glycine at this connection (10). Possible explanations for the relative contribution of d-serine and glycine in gating mature NMDARs were recently given by two recent studies. First, it was shown at hippocampal SC–CA1 synapses that d-serine would target GluN1/GluN2A-containing NMDARs, which are preferentially present within the synapse, whereas glycine would rather target GluN1/GluN2B-containing NMDARs located extrasynaptically (10). Second, it was proposed that the identity of the effective coagonist at synapses could depend on synaptic activity levels with tonic activation of NMDARs under low-activity conditions supported by ambient d-serine, whereas glycine will contribute in response to enhanced afferent activity (11).So far, most studies have explored the functions of d-serine vs. glycine at excitatory synapses in the adult brain or during aging (8) where GluN2A-expressing NMDARs prevail (1). Intriguingly, the respective role of the coagonists during postnatal development awaits to be addressed. Considerable evidence indicates that the NMDAR composition at excitatory synapses undergo an experience-dependent developmental switch from primarily GluN2B to GluN2A subunits during the first 2 wk of maturation and refinement of cortical circuits in the postnatal brain (1, 12–14). However, how this developmental switch is controlled is still elusive, and we do not know how it could be regulated or associated to the action of a preferred coagonist.The present study aimed at investigating the relative synapse specificity and the time window at which d-serine and glycine enter in function to drive NMDAR activity of developing and mature excitatory synapses in the hippocampus. In particular, we sought to elucidate whether the preference for one of the two coagonists could be related to any of the GluN2 subtypes of NMDARs. |
