Developmental aspects of the basal ganglia and therapeutic perspectives

Development and sex hormones play an important role in the expression of seizures. Sex-specific differences in the development of seizuresuppressing neuronal networks may account, at least in part, for age- and sex-related susceptibility to seizures. The substantia nigra pars reticulata is a site involved in the control of seizures. In adult male rats, there are two distinct GABA_A sensitive regions within the substantia nigra pars reticulata, which mediate opposite effects in flurothyl seizures. Muscimol infused into the anterior region is anticonvulsant while similar infusions into the posterior region are proconvulsant. These two regions differ morphologically, and utilize different efferent networks. In contrast, in postnatal day 15 male rats, there is no such differentiation and muscimol infusions have only proconvulsant effects. The hallmark of the female substantia nigra pars reticulata is the fact that muscimol-mediated proconvulsant effects cannot be demonstrated in any region at any age. The sex-related difference in nigral seizure control may be related to the lack of testosterone in females. Accordingly, neonatal castration of males results in the loss of the "proconvulsant" region. The "male" type of the substantia nigra pars reticulata effects can be induced by exogenous testosterone administration in neonatally castrated male or in female rats. The phenotype of nigral GABAergic neurons, as characterized by GABA_A receptor subunit composition, muscimol-induced electrophysiological responses, and connectivity of output networks may each be altered by the presence of testosterone. Better understanding of the influence of the endocrine system on brain development and neuronal activity may provide new insight into the treatment of age- and sex-dependent seizure disorders.