Abstracts

Rationale: Neurosteroids plays a key role in catamenial epilepsy, the cyclical occurrence of seizure exacerbations during particular phases of the menstrual cycle in women with epilepsy. Recent work has demonstrated a successful mouse model of catamenial epilepsy using a neurosteroid withdrawal paradigm. Neurosteroids act on all GABA-A receptor isoforms, but cause large effects on delta-subunit extrasynaptic receptors that mediate tonic inhibition. We have identified a novel GABA-A receptor mechanism for catamenial epilepsy. However, the functional role of delta-subunit GABA-A receptors in the pathophysiology of catamenial epilepsy remains unclear. In this study, we utilized mice lacking extrasynaptic delta-GABA-A receptor (dKO) mice to investigate whether targeted loss of tonic inhibition within the brain affects catamenial seizure susceptibility. Methods: We utilized adult female mice lacking delta-subunit GABA-A receptors. Female ?KO mice were subjected to hippocampus kindling until they exhibit stage 5 seizures. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Results: Fully kindled dKO mice subjected to neurosteroid withdrawal showed significantly increased generalized seizure frequency and intensity, and enhanced seizure susceptibility when compared to wildtype mice that experienced similar NSW. Moreover, dKO mice likewise showed reduced benzodiazepine sensitivity, but in contrast, little change in neurosteroid potency. The increased susceptibility to seizures and alterations in antiseizure drug responses are consistent with changes in the abundance of the delta-GABA-A receptors in the hippocampus. Conclusions: Collectively, these findings indicate that extrasynaptic delta-GABA-A receptors in the hippocampus play a protective role in catamenial seizures in females. These studies further reinforces the tonic inhibition-based 'neurosteroid replacement therapy' for catamenial epilepsy. Funding: Supported by NIH grant NS051398