Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists.
By Thomas Papouin, Laurent Ladépêche, Jérôme Ruel, S. Sacchi, Marilyne Labasque, Marwa Hanini, L. Groc, L. Pollegioni, J. Mothet, Stephane Oliet. Cell, 2012
712 citations recorded by the source corpus.
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.
Subfields: Biochemistry, Cellular and Molecular Neuroscience, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/d9b4751cedf730428b538438d09afceb620a2679
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Citations in the corpus
- Regulation of extrasynaptic signaling by polysialylated NCAM: Impact for synaptic plasticity and cognitive functions (2017, background): “Previous studies also suggested that activation of GluN2A-NMDARs might preferentially promote the induction of LTP, while GluN2B-contianing NMDARs mediate the induction of LTD (Liu et al., 2004; Massey et al., 2004; Papouin et al., 2012).”
- Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence? (2015, background): “Also in hippocampal slices, Papouin et al. determined, using D-serine and glycine degrading enzymes, that D-serine serves as a co-transmitter for synaptic NMDA receptors on CA1 neurons whereas glycine serves as the endogenous co-agonist for extrasynaptic NMDA receptors (Papouin et al., 2012).”
- Astrocytes: Orchestrating synaptic plasticity? (2015, neutral): “…state! rate! of! gliotransmitter! release! from! the! astrocyte! for!which! the! synaptic! release! probability! at! rest! equals! the! threshold! value! for! the! switch! between! facilitation!and!depression,!i.e.!b(ψθ)!=!bθ,!and!reads:! ψθ = bθ − b a (b − bθ )τ a + J(α − bθ )τ g⎡⎣ ⎤⎦ !”
- Role of glutamate and NMDA receptors in Alzheimer’s disease (2016, neutral): “Moreover, synaptic and extrasynaptic NMDARs were found to be activated by different endogenous coagonists, D-serine, and glycine, respectively [60].”