Abstracts

RATIONALE: The substantia nigra pars reticulata (SNR)-mediated seizure control has sex- and age-dependent features. Previous [italic]in vivo[/italic] studies show that muscimol SNR infusions are proconvulsant in male rats younger that 21 days but without effect in females of the same age. In this study, we investigated possible sex-dependent cellular effects of the GABAergic agonist muscimol on individual SNR neurons to identify a cellular substrate which may contribute to the [italic]in vivo[/italic] observations.
METHODS: Sagittal slices from PN 14-17 male and female Sprague Dawley rats were obtained using a sucrose-based buffer and a vibratome and perfused in oxygenated (95% O[sub]2[/sub]/ 5% CO[sub]2[/sub]) artificial cerebro-spinal fluid at room temperature. Visually-guided recordings from SNR neurons were performed using the technique of whole cell perforated patch clamp recording with the cation-permeable ionophore gramicidin to avoid perturbations of intracellular chloride by the electrode. Muscimol (10[mu]M) was dissolved in ACSF and bath-applied.
RESULTS: There were no significant differences between SNR neurons from male and female rats in baseline properties of resting potential, input resistance, I-V curves, spontaneous firing rate or firing in response to injected depolarizing currents. Application of muscimol led to a cessation of spontaneous action potential firing in all neurons in one to two minutes. There was, however, a significant difference in the membrane potential to which neurons were driven by muscimol: all male neurons were depolarized (range -45 to -58 mV) and all female neurons hyperpolarized (range -65 to -80 mV). Washout of muscimol led to a gradual resumption of spontaneous and current-evoked action potential firing. The resumption was significantly faster in males, with all neurons firing in response to +100pA injected current in less than 15 min of washout while none of the female neurons began firing before 25 min.
CONCLUSIONS: (1) Male SNR neurons are depolarized and female SNR neurons are hyperpolarized in response to muscimol application, implying a high and a low intracellular [Cl^-] respectively. (2) The muscimol-induced inhibition of action potential firing is significantly more pronounced in females. These differences may contribute to the sex-specific effects of [italic]in vivo[/italic] GABA[sub]A[/sub] agonist infusions in SNR.
Support: Supported by NINDS NS 20253 and NS 36238.