The long term goal of this research is to understand from a cellular and molecular perspective how specialized synaptic sites are generated, maintained, and regulated. The specific focus is to elucidate mechanisms underlying neurotransmitter receptor (ligand-gated ion channel) localization to postsynaptic sites in central neurons. A major finding in the previous award period is that synaptic receptor clustering is regulated by activity, such that postsynaptic response undergoes bomeostatic regulation. The current proposal focusses on activity regulation of two major receptor classes, the excitatory NMDA type glutamate receptor (NMDAR) and the inhibitory GABAA receptor (GABAR). For both receptor types, chronic treatment with receptor antagonists induces up-regulation of synaptic receptor whereas chronic enhancement of receptor activity induces down-regulation of synaptic receptor. For NMDAR, this regulation is post-translational and occurs through phosphorylation events. The first specific aim is to further elucidate cellular mechanisms and signal transduction events that mediate this activity-dependent redistribution of NMDAR.
Aim 2 will address molecular mechanisms, namely which regions of the NMDAR are necessary and/or sufficient for activity-regulated synaptic targeting.
Aim 3 will determine the effects of NMDAR redistribution on synaptic physiology, including a direct comparison of receptor clustering assessed immunocytochemically with synaptic receptor function. Compared with excitatory receptors, little is known about mechanisms regulating synaptic targeting of inhibitory GABA receptors.
The final aim i s to determine cellular and molecular mechanisms of activity regulation of synaptic GABAR levels. This research will contribute to understanding synapse formation and plasticity between central neurons, during normal development and under pathological conditions. Brain damage induced by epilepsy, stroke, and many neurological disorders is intimately controlled by the balance between excitatory glutamatergic and inhibitory GABAergic pathways, and in particular by calcium entry through NMDA receptors. This research on the cellular and molecular mechanisms of activity regulation of synaptic NMDA and GABA receptors is likely to lead to better therapeutic approaches to these neurological disorders.
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