Abstracts

Rationale: Stress is a common precipitating factor for seizures and stress hormones are known to be proconvulsant. Given that cortisol levels are elevated in epileptic patients and are further increased following seizures suggests that the stress hormones may contribute to acute seizure susceptibility and that modulation of the hypothalamic-pituitary-adrenal (HPA) axis may be a therapeutic target for seizure control. The major output of the HPA axis is the parvocellular, corticotropin-releasing hormone (CRH) neurons of the paraventricular nucleus (PVN) of the hypothalamus, which are largely under GABAergic control. We hypothesize that seizure-induced alterations in the GABAergic control of CRH neurons may underlie activation of the HPA axis following seizures and potentially contribute to future seizure susceptibility. Methods: We recently demonstrated that excitatory actions of GABA on CRH neurons are critical to mount the physiological response to stress. We have identified that the excitatory actions of GABA on CRH neurons are due to a collapse of the chloride gradient resulting from dephosphorylation of KCC2 residue Ser940, resulting in downregulation of KCC2. Further, excitatory actions of GABA on δ subunit-containing GABAA receptors (GABAARs) play a role in mediating the stress response. In order to determine whether activation of the HPA axis plays a role in acute seizure susceptibility, we generated a mouse model in which the GABAAR δ subunit is knocked out specifically in CRH neurons (Gabrd/CRH mice). Results: These mice exhibit blunted corticosterone levels in response to seizures induced with kainic acid. The blunted corticosterone response in Gabrd/CRH mice is associated with decreased seizure susceptibility in these animals compared to Cre-/- littermates. Administration of exogenous corticosterone restores seizure susceptibility to Cre-/- levels. Conclusions: These data suggest that activation of the stress response plays a role in acute seizure susceptibility and HPA axis modulation may be a target for seizure control.