Abstracts

The incidence of absence epilepsy is higher in females, however, the underlying reasons for this gender asymmetry are unknown. We reported previously that the expression of GABA[sub]A[/sub] receptor subunit [gamma]2 protein levels were decreased in thalamic reticular (nRt) and ventrobasal (VB) nuclei in a group of adult rats (both male and female) after perinatal treatment with a cholesterol synthesis inhibitor (CSI) AY9944 (Li et al., 2006). We performed studies to evaluate the expression of GABA[sub]A[/sub] receptor [alpha]1 and [gamma]2 subunits in thalamic nRt-VB nuclei and somatosensory cortex from male and female rats at ages p35-60 days., Experiments were carried out according to protocols approved by the Stanford Institutional Animal Care and Use Committee. Long-Evans rats were treated with AY9944 (15 mg/kg each) at p1, p5 and p9. Thalamic nRt-VB region, and somatosensory cortex were harvested at p35 and p60. Real-time PCR quantification and Western blot techniques, normalized to control group levels were performed to measure the expression of mRNA and protein levels for [alpha]1 and [gamma]2 subunits. Statistical analysis used t-tests with validation on data normalized by log transformations., Real-time PCR and Western blot results showed a gender differential effect of perinatal CSI treatment on expression of GABA[sub]A[/sub] receptor [alpha]1 and [gamma]2 subunit mRNA and protein levels in thalamus. At p35, [gamma]2 subunit mRNA levels were decreased in female (control, 1.00 [plusmn] 0.04 vs. CSI model, 0.77 [plusmn] 0.07, p [lt] 0.02) but not in male thalamus. Corresponding to the decrease of mRNA expression, [gamma]2 protein levels also were decreased in female rats previously given AY9944 (control, 1.00 [plusmn] 0.07 vs. CSI model, 0.82 [plusmn] 0.04, p [lt] 0.02). At p60, no significant difference was detected in the expression of [alpha]1 or [gamma]2 mRNAs. However, reductions of expression of [alpha]1 subunit protein levels were seen in female thalamus (control 1.00 [plusmn] 0.04 vs. CSI model 0.79 [plusmn] 0.04, p [lt] 0.02), but not in male rats. At P60, expression of GABA[sub]A[/sub] receptor [gamma]2 subunit protein also was decreased in the female, but not in the male, thalamus (control 1.00 [plusmn] 0.06 vs. CSI model 0.71 [plusmn] 0.05, p [lt] 0.01). In contrast, the expression of [gamma]2 subunit protein in CSI model somatosensory cortex was increased in both female and male cortex at age p60, compared to age-matched control somatosensory cortex (female control 1.00 [plusmn] 0.06 vs. CSI model 1.15 [plusmn] 0.06, p [lt] 0.03; male control 1.00 [plusmn] 0.02 vs. CSI model 1.21 [plusmn] 0.06, p [lt] 0.02)., Perinatal inhibition of cholesterol synthesis differentially alters GABA[sub]A[/sub] receptor subunit expression in male and female rats, demonstrating a decrease of [gamma]2 subunits in female, but not male, thalamic nRt-VB nuclei. Such changes may partially explain the higher incidence of clinical absence epilepsy in female patients., (Supported by Maslah Saul MD Chair and the James and Carrie Anderson Fund for Epilepsy Research (RSF). Susan Horngren Fund and the Epilepsy Foundation (HL). Wyeth-Ayerst for supplying the AY9944 drug.)