The objective of this work is to increase our understanding of fundamental neurochemical processes that underlie retinal physiology and pathology. Polyamines are a class of molecules present in high concentrations in the nervous system, but little is known of their specific neural functions. Recent work indicates that polyamines modulate the biochemical and electrophysiological properties of NMDA receptors. These receptors are excessively stimulated with ischemic insult to the CNS and NMDA receptor activation results in neuronal degeneration. The polyamines are likely to be involved in both the physiology of excitatory synaptic transmission and the pathology of excitotoxicity. Studies on the distribution, release, and biochemical and electrophysiological effects of polyamines are proposed. The hypothesis to be examined is: do the polyamines endogenously present in neural tissue serve as neurotransmitters/neuromodulators and if so, do they have a potentially protective role in ischemic retinal disease. Autoradiographic and immunochemical techniques will be used to determine which retinal cells and. subcellular regions contain polyamines. The release of polyamines from retina by depolarizing conditions and neurotransmitters will be studied, and the effects of light on polyamine release determined. How polyamines affect the stimulated release of neurotransmitters, and the biochemical proper-ties of NMDA receptors in retina will be determined. The effects of polyamines on retinal neurotoxicity induced by excitatory amino acids and anoxia will be examined using an in vitro model system. Effects of polyamines on currents elicited by NMDA on retinal ganglion and amacrine cells will be measured using whole-cell patch clamp techniques. Effects of polyamines on synaptically-mediated light response s and the possible role of endogenously released polyamines in these responses will also be studied with whole-cell patch clamp techniques. These studies will provide an understanding of the anatomical, biochemical, and electrophysiological properties of a novel neurotransmitter/neuromodulator system in the retina. The results of these studies may lead to new treatment modalities for many ischemic disease processes that lead to retinal neuronal degeneration, including glaucoma diabetic retinopathy, and ischemic optic neuropathy.
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