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 low density hippocampal culture system will be used in which NMDA and AMPA-selective glutamate and GABAa receptors cluster opposite terminals releasing the corresponding transmitters. NMDA receptor localization to synapses is regulated by activity. The first specific aim will determine the molecular mechanisms of the activity-dependent distribution, whether it occurs by selective expression of an NMDA receptor subunit, or phosphorylation, or association with specific binding proteins.
Aim 2 will determine more general cellular mechanisms of ligand-gated ion channel localization to postsynaptic sites: the function of input from the presynaptic terminal, the role of the actin cytoskeleton, and the stability of postsynaptic sites over time.
The final aim will test the function of the specific molecules agrin, PSD-95, and alpha-actinin in formation of postsynaptic sites in hippocampal neurons. Glutamate and GABA are the major excitatory and inhibitory transmitters in the central nervous system, and proper localization of their receptors is an integral part of brain function. In spite of the wealth of information about synaptogenesis at the neuromuscular junction, little is known about the molecular events underlying synapse formation and plasticity between central neurons, during normal development or under pathological conditions. Brain damage induced by epilepsy and stroke is intimately controlled by the balance between excitatory glutamatergic and inhibitory GABAergic pathways, and in particular by calcium entry through NMDA receptors. NMDA receptor antagonists have been used experimentally for treatments for prevention of ischemic brain damage, a therapy that has recently entered clinical trials. This research on the molecular mechanisms of upregulation of synaptic NMDA receptors by such antagonists is likely to lead to better therapeutic approaches to these neurological disorders, as well as to a better overall understanding of synapse formation and plasticity between central neurons.
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