Abstract

Catamenial epilepsy is caused by fluctuations in progesterone-derived GABAA receptor-modulating anticonvulsant neurosteroids such as allopregnanolone that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy using the neurosteroid withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (mid-luteal phase), and increases during their withdrawal (perimenstrual periods) in close association with GABAA receptor plasticity. A chronic seizure condition was created using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully-kindled mice. Fully-kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity, and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the α4- and δ-subunits of GABAA receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly due to specific changes in GABAA receptor subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for investigation of disease mechanisms and new therapeutic approaches.