This research is aimed at understanding the regulation of the GABAa receptor (GABAaR) expression in the hippocampus and cerebellum of the rat brain associated to normal aging. Approximately 30-40% of the brain synapses are GABAergic. Nevertheless, the role of GABA and GABAaR in aging has seldom been studied in spite of suggestive data indicating the existence of changes in GABA and GABAaR during normal aging. One of the main reasons for the scarcity of studies in this area has been the absence of appropriate tools other than specific receptor radioligands. The recent development in the applicants laboratory of monoclonal and polyclonal antibodies and cDNA probes for the different receptor subunits will allow them to approach the role of GABAaR in aging in a very effective way. The applicants have already provided evidence and studied the aging-related changes in some GABAaR subunits and GAD expression in some areas of the brain. The techniques involved are I) quantitative in situ, northern and dot blot hybridization for studying the mRNA expression of receptor subunits; II) quantitative immunocytochemistry, immunoblotting and immunoprecipitation for studying the protein expression; III) quantitative radioligand autoradiography for studying the ligand binding specificities of the receptor since it is expected that changes in receptor subunit composition leads to changes in binding affinities for some ligands. In addition, deafferentation models of the hippocampus and cerebellum will be used to test the hypothesis that some of the aging-related changes in GABAaR subunit expression are due to changes in neuronal connectivity. The possible involvement of neurotrophins and their receptors in the regulation of GABAaR subunit expression will also be investigated. These studies are directly relevant to aging in several ways: I) Much of the physical and mental deterioration associated with aging is due to impairments in brain physiology. Results obtained in our laboratory as well as in others indicate that the GABAaR change during aging. II) Memory, frequently is impaired during aging. Published results have shown the importance of the hippocampal GABAaR for the consolidation of memory. III) Benzodiazepines (ie. Librium and Valium) exert their action by binding to the GABAaR. Sleep disorders frequently accompany aging. Benzodiazepines are widely used to treat sleep disorders. IV) The GABAaR are also involved in the control of blood pressure and in areas of the brain involved in sensory-motor coordination, hearing and vision. In addition, the GABAaR are prominently involved in the physiology of the retina. Vision, hearing and motor coordination are frequently impaired during aging. V) Understanding of the aging-related changes in GABAaR subunit composition and ligand binding will help to develop drugs that would recognize specific types of GABAaR involved in an aging-related impaired function without affecting other GABAaR involved in other brain functions, thus eliminating most of the drug side-effects.
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