Abstracts

Rationale: Enduring effects of early-life stress on the brain promotes vulnerability to the later development of experimental limbic epilepsy. This process is possibly mediated by hyper-reactivity of the hypothalamic-pituitary-adrenal (HPA) axis with increased corticosterone release. Using the maternal separation (MS) model of early-life stress in rats, this study assessed whether inhibiting corticosterone synthesis could ameliorate the adverse effects of MS stress on kindling epileptogenesis. Methods: From postnatal days 2-14, Wistar rats were subjected to MS stress for 3h/day (MS, n=17) or early-handling for 15min/day (EH, n=21). At 8weeks, female rats were assessed for seizure threshold via a bipolar electrode implanted in the left amygdala, and subsequently subjected to after-discharge threshold testing and electrical amygdala kindling. Throughout the kindling period, rats were administered either metyrapone (corticosterone synthesis inhibitor: 50mg/kg ip) or vehicle 60min before each kindling stimulation. Results: Vehicle-treated MS rats displayed reduced seizure threshold compared to EH rats (p=0.03), a vulnerability attenuated by metyrapone pretreatment. During kindling, vehicle-treated MS rats also exhibited longer seizure duration compared to EH rats (p=0.02), an effect equally reversed by metyrapone treatment. Further, metyrapone treatment in MS rats retarded the progression of kindling (p=0.03). Conclusions: Inhibition of corticosterone synthesis with metyrapone alleviates the enduring effects of MS stress on seizure susceptibility and severity. This suggests that HPA axis hyper-reactivity is critical to the effect of MS stress in increasing vulnerability to limbic epileptogenesis.