Neural communication is modified throughout life by use-dependent changes in the number and function of glutamate receptors at excitatory synapses. Among the glutamate-gated ion channels, N-methyl-D-aspartate (NMDA) receptors play a central role in synapse formation, synaptic plasticity, neurological diseases, and psychiatric disorders including addiction. A principal mechanism controlling NMDA receptor signaling is accurate regulation of the number of NMDA receptors present at the synapse. Although most widely appreciated for AMPA-type glutamate receptors, dynamic regulation of the number of postsynaptic NMDA receptors is increasingly recognized as an integral feature of synapse maturation and synaptic plasticity. And yet, little is known about the molecular mechanisms for trafficking NMDA receptors to and from the synapse. To address these important questions, my laboratory has initiated a program of biochemical and cell biological studies to analyze the trafficking of NMDA receptors and the regulation of such trafficking by neuronal activity. We have recently found that export from the endoplasmic reticulum (ER) serves as an activity-dependent checkpoint for the synaptic delivery of NMDA receptors, Moreover, we have identified key molecular determinants within NMDA receptor subunits that control forward trafficking, and developed optical imaging approaches to visualize secretory trafficking in living dendrites. Taking advantage of these preliminary data, we propose to define the underlying cellular mechanisms that control NMDA receptor secretory trafficking, and to determine how activity directs NMDA receptor intracellular transport to effect synapse modification. This work will provide much-needed insight into fundamental mechanisms of synapse formation and plasticity. Moreover, because NMDA receptors participate in the pathogenesis of a wide range of neurologic disorders, psychiatric disease, and states of addiction, these studies hold promise for the development of novel therapeutic strategies.
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