Learning from NMDA receptor trafficking: clues to the development and maturation of glutamatergic synapses

Activity-dependent changes in excitatory transmission allow the brain to develop, mature, learn and retain memories, and underlie many pathological states of the central nervous system. A principal mechanism by which neurons regulate excitatory transmission is by altering the number and composition of glutamate receptors at the postsynaptic plasma membrane. The dynamic trafficking of glutamate receptors to and from synaptic sites involves a complex series of events including receptor assembly, trafficking through secretory compartments, membrane insertion and endocytic cycling. While these events have become widely appreciated as critical processes regulating AMPA-type glutamate receptors during synaptic plasticity, the mechanisms that control the trafficking of NMDA-type glutamate receptors (NMDARs) are only now beginning to be understood. Until recently, NMDARs were considered immobile receptors, tightly anchored to the postsynaptic membrane. Here, we review recent evidence that challenges this view, focusing on the role that activity plays in altering NMDAR trafficking and how such dynamic regulation of NMDARs may impact on the plasticity of neural circuits.