Abstracts

Rationale: We recently demonstrated that seizures activate the HPA axis, increasing circulating levels of corticosterone. Given the well-established proconvulsant actions of corticosterone, we hypothesize that seizure-induced activation of the HPA axis may contribute to further seizure susceptibility.Methods: To test this hypothesis, we evaluated the antiseizure effects of blocking the seizure-induced activation of the HPA axis with the corticotropin releasing hormone (CRH) antagonist, Antalarmin. Further, we generated mice with loss of the GABAA receptor d subunit in CRH neurons (Gabrd/Crh mice), which exhibits HPA axis hypofunction due to the excitatory actions of GABA involved in activation of the HPA axis. We utilized these pharmacological and genetic manipulations of the HPA axis to determine the effects on acute seizure susceptibility in response to kainic acid (KA; 10mg/kg or 20mg/kg, i.p.) using in vivo EEG recordings in awake, behaving mice. The latency to seizure onset and the percent time exhibiting epileptiform activity was measured for two hours following KA administration. In addition, we investigated the impact of seizure-induced activation of the HPA axis on epileptogenesis and seizure frequency in chronically epileptic mice using the pilocarpine model (340mg/kg, i.p.). Long-term (24/7) continuous video, EEG recordings were performed from 3 – 6 weeks post-status epilepticus (SE). The number of seizures per day was calculated in Gabrd/Crh mice and Cre-/- littermates over a 21-day period. Depression-like behavior associated with epilepsy was also assessed in chronically epileptic Gabrd/Crh mice and Cre-/- littermates compared to seizure-free controls. The impact of exogenous corticosterone administration (21-day, 10mg slow-release pellet) on both seizure susceptibility and depression-like behaviors was also assessed.Results: Seizures induced with i.p. kainic acid, i.p. pilocarpine, or intrahippocampal administration of kainic acid activates the HPA axis, evident by increased c-fos expression in the PVN and increased circulating levels of corticosterone. Suppression of seizure-induced activation of the HPA axis with either Antalarmin treatment or in Gabrd/Crh mice decreases epileptiform activity induced by acute administration of kainic acid. Seizure frequency is also decreased in chronically-epileptic Gabrd/Crh mice compared to Cre-/- littermates. Decreased seizure-induced activation of the HPA axis in Gabrd/Crh mice is associated with decreased depression-like behavior in chronically epileptic mice. Exogenous administration of corticosterone to Gabrd/Crh mice increases both seizure frequency and depression-like behaviors.Conclusions: These data demonstrate that seizure-induced activation of the HPA axis increases acute seizure susceptibility and increases seizure frequency in chronically epileptic mice. Further, these findings suggest that targeting the HPA axis may be a useful add-on therapy for seizure control and the comorbidity of epilepsy and depression.