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

Matildé Le Bail, Magalie Martineau, Silvia Sacchi, Natalia Yatsenko, Inna Radzishevsky, Sandrine Conrod, Karima Ait Ouares, Herman Wolosker, Loredano Pollegioni, Jean Marie Billard, Jean Pierre Mothet, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)E204-E213
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number2
StatePublished - Jan 13 2015


  • Coagonist
  • Developmental switch
  • Hippocampus
  • NMDA receptors
  • Synapse

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Identity of the NMDA receptor coagonist is synapse specific and developmentally regulated in the hippocampus'. Together they form a unique fingerprint.

Cite this