NMDAR-Activated PP1 Dephosphorylates GluN2B to Modulate NMDAR-Plasticity

In mature neurons, postsynaptic NMDARs are segregated into two populations, synaptic and extrasynaptic NMDARs, 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 (NMDAR-plasticity). 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 subsynaptic localization. We find that this phosphorylation maintains NMDARs segregated at extrasynaptic membranes as part of a protein complex containing inactive Protein Phosphatase 1 (PP1). Global activation of NMDARs lead 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 activity-dependent NMDAR-plasticity in mature neurons, a process with profound consequences for synaptic and structural plasticity, metaplasticity, and synaptic neurotransmission.