AI Article Synopsis

  • - N-methyl-d-aspartate receptors (NMDARs) in the brain operate in two different locations—synaptic and extrasynaptic—and are involved in various physiological and pathological processes.
  • - Different coagonists, d-serine for synaptic and glycine for extrasynaptic NMDARs, are required for their activation, and this segregation affects NMDAR behavior and location within cells.
  • - Synaptic NMDARs are specifically linked to long-term potentiation and neurotoxicity, while both synaptic and extrasynaptic receptors are necessary for long-term depression, highlighting their distinct roles in brain function.

Article 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.

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http://dx.doi.org/10.1016/j.cell.2012.06.029DOI Listing

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