This is a competing renewal application requesting continuing support for studies pertaining to ischemic neurodegeneration in the vertebrate retina. Over the last several years the applicants have developed an isolated chick embryo retina model and an adult rat dye/photothrombosis model of retinal ischemia. Using these models, we have examined in detail acute mechanisms of ischemic neurodegeneration, and have found that blockade of specific subtypes of excitatory amino acid (EAA) receptors protects against these acute mechanisms. An additional major emphasis of our research has been on modifying retinal ischemia models to make them optimally suited for studying mechanisms of delayed or slowly evolving ischemic retinal degeneration. In order to make the chick embryo retina model more suitable for studying delayed mechanisms, we have modified the protocol to permit in vitro incubation for periods up to 24 hours after the ischemic insult. Experimental manipulations can be performed before, during or after ischemic exposure. In addition, we have begun using a biochemical method of quantifying neuronal death in the chick retina by measuring release of the intracellular enzyme, lactate dehydrogenase (LDH). To study delayed ischemic neurodegeneration in vivo we have begun working with an adult rat intraocular hypertension model that permits reversible occlusion of the retinal blood supply so that the duration of ischemia can be varied with blood supply being restored in the post-ischemic interval and neuroprotective drugs being introduced at any time before, during or after the ischemic episode. In addition, we have developed immunocytochemical methods for studying which retinal cell types are most sensitive and which most resistant to ischemic degeneration. Goals of the proposed research are to continue studying mechanisms of delayed ischemia neurodegeneration and methods for protecting against such degeneration in the isolated developing chick retina (Aim #1) and in the in vivo adult rat retinal (Aim #2), and to develop antibodies against recently cloned EAA receptors to use as anatomical and biochemical tools for studying retinal ischemic neurodegeneration (Aim #3). The latter aim takes advantage of the fact that a multitude of EAA receptor subunits have been cloned and sequenced in the past two years, making it possible to develop antibody probes for anatomical localization of each receptor subtype at the cellular and subcellular (synaptic membrane) level in the retina. We propose to use both light and electron microscopic immunocytochemical methods for studying how these receptor subtypes are normally distributed in the retina and how an ischemic insult alters the distribution pattern for each receptor subtype. It is anticipated that an ischemic insult will be associated with loss of the specific EAA receptor subtypes that are instrumental in mediating the ischemic damage.
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