Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function

Research over the last few decades has shaped our understanding of the crucial involvement of the N-methyl-d-aspartate receptor (NMDAR) in mediating excitatory synaptic neurotransmission, neuronal development and learning and memory. The complexity of NMDAR modulation has escalated with the knowledge that receptors can traffic between synaptic and extrasynaptic sites, and that location on the plasma membrane profoundly affects the physiological function of NMDARs. Moreover, mechanisms that regulate NMDAR subcellular localization and function, such as protein–protein interactions, phosphorylation, palmitoylation, ubiquitination and receptor proteolytic cleavage, may differ for synaptic and extrasynaptic NMDARs. Recent studies suggest that NMDAR mislocalization is a dominant contributing factor to glutamatergic dysfunction and pathogenesis in neurological disorders such as Huntington's disease, Alzheimer's disease and ischemia. Therapeutic approaches that specifically rectify receptor mislocalization or target resulting downstream apoptotic signaling could be beneficial for preventing disease onset or progression across many disorders that are commonly caused by NMDAR dysfunction. This review will summarize the molecular mechanisms that regulate synaptic and extrasynaptic NMDAR localization in both physiologic and pathogenic states.