Steroid hormonal regulation is critical for normal brain development and may play an important role in human seizure disorders. The substantia nigra pars reticulata (SNR) is one of the structures controlling the spread of seizure activity via its GABAergic neurotransmission especially through GABAA receptors. The SNR is functionally subdivided into anterior and posterior regions which mediate opposing effects of muscimol (a GABAA receptor agonist) on fluorothyl seizures. Muscimol infusions in the SNRanterior produce anticonvulsant effects, while similar infusions in the SNRposterior produce proconvulsant effects. Preliminary data show that the functional maturation of these two SNR regions may be under gonadal steroid hormonal control. In neonatally castrated m ale rats there is accelerated maturation of the """"""""anticonvulsant"""""""" SNRanterior. Neonatal castration does not influence the emergence of the """"""""proconvulsant"""""""" SNR region. Furthermore, in female rats there is no functional segregation of the SNR because muscimol infusions produce anticonvulsant effects irrespective to injection site. Therefore, the presence of testosterone early in life may be responsible for the functional segregation of the SNR. The following hypotheses will be tested: In male rats, early postnatal depletion of testosterone accelerates the development of the """"""""anticonvulsant"""""""" SNRanterior region. In male rats, the emergence of the """"""""proconvulsant"""""""" SNRposterior region is independent of early postnatal testosterone. The two SNR regions in neonatally castrated rats have similar features as the two SNR regions in normal male rats (the term features denotes responsivity to GABAergic agents and output networks). Lack of prenatal testosterone leads to the female type of the SNR with only one GABAA sensitive SNR region. The female SNR may have similar features with the mature male """"""""anticonvulsant"""""""" SNRanterior. The prenatal testosterone surge is responsible for the development of the """"""""proconvulsant"""""""" SNR region. Methods include early postnatal castration and hormone replacements, localized infusions of GABAA agonists and antagonists, flurothyl seizure testing and [14C] deoxyglucose autoradiography. Rats of both sexes and various ages will be used. These studies may lead to the development of new antiepileptic treatments that take into the account sexual age-related differences.
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