This research application represents a broad investigation into the mechanisms of cell communication in the vertebrate retina. Our objectives are centered on three main issues. These include (1) the mechanisms in the inner retina which are subserved by the release of glutamate and the different types of glutamate receptors, both ionotropic and metabotropic, which interact to regulate the excitability of ganglion cells; (2) the identification and biophysical characterization of voltage-gated Ca2+ channels in ganglion cells with special emphasis on T-type Ca2+ channels, their pharmacological properties and cellular distribution in the dendrites and soma. We plan to evaluate how T-type Ca2+ channels contribute to nerve impulse generation and whether these ion channels play a role in amplifying synaptic currents which are generated on the dendrites. The third broad mission of this application is dedicated to a better understanding of dendritic physiology by recording from dendrites and isolated dendrosomes to further define the physiological properties of AMPA, NMDA and KA receptors. The methods used in this study will include electrophysiology, Ca2+ imaging and the use of photolysis to introduce chemical agents quickly and apply them locally at visually targeted dendritic regions. These experiments will be carried out in the amphibian retina and are designed to enhance our understanding about the mechanisms by which cells interact with one another and contribute to the excitability of retinal ganglion cells. The health-related implications of this research are extensive and relate to the mechanisms which control cellular functions of ganglion cells and how these mechanisms may help or hinder the stability of these cells when confronted with the stress of several different disease states, including glaucoma and diabetic retinopathy.
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