The objective of this proposal is to identify mechanisms involved in the suppression of seizures as a function of age. The increased seizure susceptibility of the immature brain may be due to absence of networks that develop with age and ultimately suppress seizures in adults Ongoing studies suggest that in the adult substantia nigra (SN) there are two topographically discrete GABAA- sensitive regions which differ in the mRNA expression of the GABAA receptor alpha subunit. These two regions alter metabolism in divergent ngral projections and mediate opposing effects on seizures demonstrating the existence of separate anticonvulsant and proconvulsant SN networks. This nigral topographic arrangement occurs with maturation. It is not present in two week old rats in which only the proconvulsant system is functioning.
The first aim i s to determine in adult rats the characteristics of the two GABAA sensitive nigral networks by determining the localization, connectivity and characteristics of the neurons in the regions that mediate the opposing nigral effects on seizures and whether the effects of the two regions on seizures are specific for the GABAA- system.
The second aim i s to determine the maturational patterns of the two networks in rats of various ages until the establishment of the adult features. Methods include localized microinfusions of GABAA, GABAB or excitatory aminoacids -agonists and antagonists and seizure testing using flurothyl, [3H] autoradiography, immunocytochemistry, tracing techniques, [14C] deoxyglucose autoradiography and in vitro receptor binding. Rats of various ages throughout development will be used to determine the maturational profIle of the SN seizure modification. The goal is to develop a better understanding of the mechanisms that participate in the suppression of seizures with maturation. These studies may lead to the development of new therapeutic treatments that will compensate for the maturational state of the CNS.
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