The overall goal is to identify mechanisms involved in the suppression of seizures. Epileptic seizures are influenced by age and gender. The substantia nigra pars reticulata (SNR) is involved in the control of seizures. In the adult male SNR there are two topographically discrete GABAA-sensitive regions which constitute separate anticonvulsant and proconvulsant SN systems. In two-week old male rats only the proconvulsant system is functioning. A key difference between male and female SNR is the presence of a GABAA sensitive region that mediates proconvulsant effects in gonadally-intact males of all ages. There is no proconvulsant region in females or in neonatally-castrated males. Daily administration of testosterone in neonatal females or neonatally-castrated males induces the emergence of the proconvulsant region. These results suggest that postnatal testosterone may control the development and sexual differentiation of the SNR. Additional data indicate sex-differences in the phenotype of SNR GABAergic neurons in terms of GABAA receptor subunit composition and in muscimol-induced electrophysiologic responses and output networks.
The specific aims are to determine: 1. The critical postnatal period during which the presence of testosterone leads to the formation of the proconvulsant SNR region; 2. Whether the testosterone effect is the result of aromatization or via its androgenic action; 3. Whether administration of testosterone (or identified effective derivatives) in female or neonatally castrated male rats during the critical period alters the phenotypic features of GABA neurons and the networks involved in SNR-mediated control of seizures; 4. Whether administration of antagonists of testosterone (or identified effective derivatives) in gonadally intact male rats during the critical period eliminates the proconvulsant region. Methods include localized microinfusions of GABAA agonists and seizure testing using flurothyl, gonadal hormone treatments, immunohistochemistry, in situ hybridization, in vitro perforated patch clamp recordings and deoxyglucose autoradiography. Gonadally-intact and neonatally castrated male rats and female rats will be used. The recognition that the SNR has sex and age-related features can be translated into the development of specific and more effective treatments of the epilepsies.
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