A chronic model of atypical absence seizures: studies of developmental and gender sensitivity

Treatment of Long Evans hooded rats during post-natal brain development with the cholesterol synthesis inhibitor, AY-9944 (AY) results in the occurrence of atypical absence seizures, which are frequent, recurrent, and life-long. AY induced slow spike-and-wave discharges (SSWD) are significantly more frequent and prolonged in female Long Evans rats than males. Three groups of experiments were performed in order to characterize further the AY model of atypical absence seizures, (1) a developmental study was performed to ascertain whether AY-induced seizures appear before or after the onset of puberty; (2) male/female differences in severity of response to AY was determined in order to answer the question whether the gender specificity was a pre- or postpubertal phenomenon; (3) a time course study was done to determine the minimum number of postnatal AY doses needed to induce the life-long atypical absence seizure state. The data indicate that AY-induced atypical absence seizures emerge before the onset of puberty. Further, we show that the gender difference in severity of AY-induced seizures also is a pre-pubertal phenomenon. Finally, a single dose of AY (7.5 mg/kg) administered on post-natal day (P) 5 was sufficient to induce SSWD on the electrocorticogram (ECoG). Our results suggest that sex hormones are important in the AY model, although the exact role of cholesterol derived steroid hormones in the regulation and maintenance of AY induced atypical absence seizures remains to be determined.