GABA-A mediated modification of seizure in ensemble systems is AGO- and gender-dependent

The immature brain is more susceptible to the development of bilateral seizures and status epilepticus than the adult brain. The substantia nigra pars reticulata may play a crucial role in the control of seizure propagation as a function of age and possibly gender. The effects of the substantia nigra pars reticulata on seizures are predominantly mediated by the GABA-A system. In the adult male substantia nigra pars reticulata, there are two regions that mediate opposing effects on seizures following bilateral infusions of GABA-A agents such as muscimol. One region is located in the anterior substantia nigra pars reticulata and muscimol infusions in that region mediate anticonvulsant effects. These anticonvulsant effects utilize a circuitry that may involve the ventromedial thalamic nucleus and superior colliculus. The second region is in the posterior substantia nigra pars reticulata and muscimol infusions produce proconvulsant effects, perhaps mediated by the striatum and the globus pallidus as well as the superior colliculus too. The sitespecific effects may be also due to differences in the expression of local GABA-A receptor subtypes. Pharmacologie studies utilizing various GABA-A agents with presumed specific effects on high- and low-affinity GABA-A receptors as well as in situ hybridization studies of GABA-A subunit mRN As support this hypothesis. Other factors such as differences in extracellular chloride homeostasis, existence of extrasynaptic receptors or receptor desensitization may play a role too. In developing male substantia nigra pars reticulata, only the "proconvulsant" region is present up to the age of 21 days. Thus, muscimol infusions produce only proconvulsant effects. Deoxyglucose studies suggest that the circuitry that mediates the proconvulsant effects of substantia nigra pars reticulata in 15-day-old male rats is similar to the circuitry that mediates the proconvulsant effects of the adult posterior substantia nigra pars reticulata. In situ hybridization studies suggest that the neurons in the developing substantia nigra pars reticulata and the adult posterior substantia nigra pars reticulata (both mediating proconvulsant effects) express lower amounts of the ocl subunit mRNA than the neurons in the adult anterior substantia nigra pars reticulata; the latter region mediates anticonvulsant effects. However, the type of the GABA-A receptors in the developing male substantia nigra pars reticulata may not be similar to the type of GABA-A receptors in adult male posterior substantia nigra pars reticulata. Determining the effects of intranigral infusions of specific high- and low- affinity GABA-A agonists and antagonists on seizures in male adult and 15-day old rats lead to this conclusion. In the male rat, the transition from the immature to mature substantia nigra pars reticulata-mediated seizure control occurs between the ages of 25 to 30 days. Studies in male rats castrated on the day of birth utilizing localized muscimol infusions indicate that testosterone depletion accelerates the development of the anterior substantia nigra pars reticulata with its anticonvulsant features. Castration also prevents the development of the proconvulsant region in the posterior substantia nigra pars reticulata. In female rats, the development of the substantia nigra pars reticulata (in terms of its effects on seizures) is not linear. Thus, muscimol infusions in the female 15-day old substantia nigra pars reticulata mediate only proconvulsant effects. By 25-days of age, infusions of muscimol in the anterior region of the substantia nigra pars reticulata produce anticonvulsant effects while similar infusions in the posterior region do not influence seizures. The data indicate that hormonal factors may have an important role in the maturation of ensemble systems involved in the containment of seizures and status epilepticus.