AGE RELATED SEIZURE SUPPRESSION

The objective of this proposal is to identify the mechanism involved in the suppression of seizures as a function of age. Ongoing studies have demonstrated that the increased seizure susceptibility of the immature brain may be due to an alteration of the functional activity of the GABA sensitive neurons in the substantia nigra (SN) and their efferent connections. The aims of the proposal are to determine: 1) the age-related differences in the development of GABA receptor substypes in the SN; 2) the role of specific GABA receptor subtypes in the SN-mediated modification of seizures in adults and rat pups; 3) the efferent pathways from the SN that mediate the different GABAergic effects on seizures in adults and rat pups. The methods include in vivo studies to determine the seizure susceptibility of adult rats and 16-day old rat pups after GABAergic pre-treatment using chronically implanted cannulae, intracranial microinfusions and the flurothyl model of epilepsy; in vitro quantitative light microscopy receptor autoradiography; and deoxyglucose autoradiographic studies to map the SN efferent pathways. The goal is to develop a better understanding of the endogenous processes involved in the modification of seizures with maturation. These studies may lead to the development of new therapeutic approaches that will compensate for the maturational state of the CNS.