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.

Center for Neuroscience University of California Davis Davis CA 95618 USA

Department of Pharmacology Feinberg School of Medicine Northwestern University Chicago IL 60611 USA

Department of Pharmacology Feinberg School of Medicine Northwestern University Chicago IL 60611 USA; Department of Cellular Neurophysiology Institute of Physiology CAS Prague 142 20 Czech Republic

Department of Pharmacology Feinberg School of Medicine Northwestern University Chicago IL 60611 USA; Department of Neurology University of California San Francisco San Francisco CA 94158 USA

Department of Physiology Feinberg School of Medicine Northwestern University Chicago IL 60611 USA

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