| Summary: | Summary: In mature neurons, postsynaptic N-methyl-D-aspartate receptors (NMDARs) are segregated into two populations, synaptic and extrasynaptic, which differ in localization, function, and associated intracellular cascades. These two pools are connected via lateral diffusion, and receptor exchange between them modulates synaptic NMDAR content. Here, we identify the phosphorylation of the PDZ-ligand of the GluN2B subunit of NMDARs (at S1480) as a critical determinant in dynamically controlling NMDAR synaptic content. We find that phosphorylation of GluN2B at S1480 maintains NMDARs at extrasynaptic membranes as part of a protein complex containing protein phosphatase 1 (PP1). Global activation of NMDARs leads to the activation of PP1, which mediates dephosphorylation of GluN2B at S1480 to promote an increase in synaptic NMDAR content. Thus, PP1-mediated dephosphorylation of the GluN2B PDZ-ligand modulates the synaptic expression of NMDARs in mature neurons in an activity-dependent manner, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission. : The dynamic regulation of synaptically expressed NMDA receptors (NMDARs) is essential for synaptic function. Here, Chiu et al. describe a mechanism controlling this process in mature neurons by showing that increases in NMDAR synaptic content are driven by PP1-mediated dephosphorylation of extrasynaptic NMDARs within their GluN2B PDZ-ligands. Keywords: NMDA receptors, NMDAR synaptic content, PP1, extrasynaptic NMDAR, dephosphorylation, GluN2B
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