This competing renewal application focuses on mechanisms by which dysfunction of the glutamate (Glu) transmitter system may contribute to either acute or chronic diseases of the retina. Accumulating evidence indicates that ischemic conditions in either the retina or brain lead to excessive activation of Glu receptors which unleashes a cascade of events resulting in excitotoxic neuronal degeneration. Using an ex vivo chick embryo retina model, the applicants have generated a great deal of information pertaining to underlying mechanisms and methods of preventing ischemic retinal neurodegeneration. However, despite its may favorable characteristics, the chick retina model is not a mammalian model and it provides information relevant to only one stage of ontogenesis. To overcome these problems, the applicants have now developed a new model which permits the mammalian (rat) retina to be isolated and studied ex vivo at any age from birth to old age. It is proposed to use this new model to study at sequential stages in ontogenesis several factors that are important determinants of retinal vulnerability to excitotoxic and/or ischemic neurodegeneration. Prompted by other recent evidence suggesting that excitotoxic mechanisms may play a role in glaucomatous retinal degeneration, experiments will be undertaken, using a rat model of glaucoma, to determine whether drugs that suppress the release of Glu, or drugs that block Glu receptors can prevent glaucomatous ganglion cell degeneration. Finally, the applicants have recently described an intriguing new retinotoxic syndrome in which the developing rodent retina ceases developing and degenerates en masse following several consecutive daily subcutaneous treatments with Glu analogs that block an intracellular phosphoinositide (PI) hydrolysis-linked second messenger system coupled to a Glu metabotropic receptor (mGluR). It is postulated that these agents exert a primary toxic action upon Muller cells which causes secondary degeneration of retinal neurons due to loss of neurotrophic support that Muller cells ordinarily provide for the developing retina. These studies will be conducted studies using Muller cell cultures to test this hypothesis.
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