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
Proc Natl Acad Sci USA. 2014-12-30; 112(2): E204-E213
DOI: 10.1073/pnas.1416668112

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1. Proc Natl Acad Sci U S A. 2015 Jan 13;112(2):E204-13. doi:
10.1073/pnas.1416668112. Epub 2014 Dec 30.

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

Le Bail M(1), Martineau M(2), Sacchi S(3), Yatsenko N(1), Radzishevsky I(4),
Conrod S(1), Ait Ouares K(1), Wolosker H(4), Pollegioni L(3), Billard JM(5),
Mothet JP(6).

Author information:
(1)Aix Marseille University, Centre de Recherche en Neurobiologie et
Neurophysiologie de Marseiille UMR7286 CNRS, F-13344 Marseille, France;
(2)Department of Cellular Biophysics, Institute for Medical Physics and
Biophysics, University of Muenster, 48149 Muenster, Germany;
(3)Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi
dell’Insubria and The Protein Factory, Politecnico di Milano, Istituto di Chimica
del Riconoscimento Molecolare Consiglio Nazionale delle Ricerche Milano, and
Università degli Studi dell’Insubria, 21100 Varese, Italy;
(4)Department of Biochemistry, The Rappaport Faculty of Medicine and Research
Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel; and.
(5)Center of Psychiatry and Neuroscience, University Paris Descartes, Sorbonne
Paris City, UMR 894, 75014 Paris, France.
(6)Aix Marseille University, Centre de Recherche en Neurobiologie et
Neurophysiologie de Marseiille UMR7286 CNRS, F-13344 Marseille, France;
*protected email*.

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.

DOI: 10.1073/pnas.1416668112
PMCID: PMC4299231
PMID: 25550512 [Indexed for MEDLINE]


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