The objective of this proposal is to identify mechanisms involved in the suppression of seizures as a function of age. Ongoing studies suggest that the increased seizure susceptibility of the immature brain may be due to age-specific differences in the GABAA receptor subtypes within the substantia nigra (SN), a site that is crucial for the control of seizures in adults.
The aims are to determine 1) whether there are differences in nigral GABAA receptor isoforms as a function of age; 2) whether there is a different functional role of nigral GABAA receptor isoforms on seizures as a function of age and drug dosage; 3) the nigral GABAA sensitive output systems involved in the modification of seizures as a function of age, drug and dose. Methods include in vitro studies (in situ hybridization histochemistry) to determine the ontogeny of particular GABAA isoforms; in vivo studies to determine the seizure susceptibility of rats of various ages after intracranial microinfusions of relatively specific GABAA agents in the SN via chronic indwelling cannulae in the flurothyl model of epilepsy; and deoxyglucose autoradiographic studies to map the nigral efferents activated by the relatively specific GABAA agents. Rats of various ages throughout development will be used to determine the maturational profile of the SN-mediated 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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