title: Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.
abstract: N-methyl-d-aspartate receptors (NMDARs) are located in neuronal cell membranes at synaptic and extrasynaptic locations, where they are believed to mediate distinct physiological and pathological processes. Activation of NMDARs requires glutamate and a coagonist whose nature and impact on NMDAR physiology remain elusive. We report that synaptic and extrasynaptic NMDARs are gated by different endogenous coagonists, d-serine and glycine, respectively. The regionalized availability of the coagonists matches the preferential affinity of synaptic NMDARs for d-serine and extrasynaptic NMDARs for glycine. Furthermore, glycine and d-serine inhibit NMDAR surface trafficking in a subunit-dependent manner, which is likely to influence NMDARs subcellular location. Taking advantage of this coagonist segregation, we demonstrate that long-term potentiation and NMDA-induced neurotoxicity rely on synaptic NMDARs only. Conversely, long-term depression requires both synaptic and extrasynaptic receptors. Our observations provide key insights into the operating mode of NMDARs, emphasizing functional distinctions between synaptic and extrasynaptic NMDARs in brain physiology.
authors.affiliation: INSERM U862, Neurocentre Magendie, 33077 Bordeaux, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Papouin
authors.forename: Laurent
authors.initials: L
authors.lastname: Ladépêche
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ruel
authors.forename: Silvia
authors.initials: S
authors.lastname: Sacchi
authors.forename: Marilyne
authors.initials: M
authors.lastname: Labasque
authors.forename: Marwa
authors.initials: M
authors.lastname: Hanini
authors.forename: Laurent
authors.initials: L
authors.lastname: Groc
authors.forename: Loredano
authors.initials: L
authors.lastname: Pollegioni
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Mothet
authors.forename: Stéphane H R
authors.initials: SH
authors.lastname: Oliet
mesh_terms: D000818:Animals; D002462:Cell Membrane; D002478:Cells, Cultured; D005998:Glycine / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D009457:Neuroglia / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D013569:Synapses
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D005998:Glycine