ACh neuroprotection against excitotoxicity in RGCs

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DESCRIPTION (provided by applicant): Excitotoxicity is the process by which excess excitatory neurotransmitter release in the central nervous system destroys neurons through an apoptotic mechanism. In the mammalian retina, excess glutamate release has been shown to be involved in retinal ganglion cell (RGC) death and is associated with several retinal disease states, including glaucoma, diabetic retinopathy and retinal ischemia. Recently, studies from this lab have demonstrated that acetylcholine (ACh) protects against glutamate-induced excitotoxicity in isolated adult pig retinal ganglion cells through activation of nicotinic acetylcholine receptors (nAChRs). However, the types of nAChRs involved in neuroprotection and the mechanism linking activation of nAChRs to neuroprotection is unknown. Base on preliminary results obtained from this lab, the hypothesis that will be tested in this proposal is that activation of nAChRs on pig RGCs initiates a signaling cascade to reduce cell death caused by glutamate-induced excitotoxicity. Three specific aims have been designed to address this hypothesis: 1) To identify and characterize the nAChR subunits associated with ACh's neuroprotective effect against glutamate-induced excitotoxicity in isolated adult pig RGCs; 2) To test the hypothesis that calcium permeation through nAChRs is required for neuroprotection to occur and 3) To test the hypothesis that second messenger pathways link nAChR activation to neuroprotection of glutamate-induced excitotoxicity. Using a combination of immunocytochemical, pharmacological, electrophysiological and calcium imaging techniques, the results obtained from this study should identify the types of nAChR subunits responsible for ACh neuroprotection in pig retinal ganglion cells and will indicate which second messenger cascades are involved in ACh's neuroprotective effect. Understanding the mechanism of AChR neuroprotection in the retina can ultimately lead to reduced cell death due to excitotoxicity and treatment for excitotoxicity- linked diseases in the retina, such as glaucoma, as well as excitotoxic-linked diseases in the CNS, such as Alzheimer's disease. In the mammalian retina, excess glutamate release has been shown to be involved in retinal ganglion cell death and is associated with certain retinal disease states including glaucoma, diabetic retinopathy and retinal ischemia. This study proposes to identify and analyze a mechanism of neuroprotection in the retina that prevents retinal ganglion cells from dying due to excitotoxicity. Understanding the mechanism of neuroprotection against excitotoxicity is essential for any future therapeutic intervention leading to treatment of excitotoxicity in the retina and other regions of the CNS. Neuroprotection treatment can ultimately improve the quality of life for millions of people in the world.