Abstracts

Rationale: Neurosteroids are endogenous regulators of seizure susceptibility especially in conditions such as catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around specific points in the menstrual cycle. Neurosteroids regulates GABA-A receptor plasticity. Neurosteroid withdrawal such as that occurs during menstruation is associated with marked increase in expression of GABA-A receptor ?4-subunit, but alterations in ?-subunit was not completely characterized. Moreover, the molecular mechanisms underlying neurosteroid withdrawal induced alterations in subunit composition remains unclear. Methods: In this study, we determined neurosteroid withdrawal induced alterations in the ?-subunit expression in the hippocampus using a mouse withdrawal paradigm. The role of progesterone receptors (PRs) was investigated utilized the progesterone receptor knockout (PRKO) mice. Animals were treated with progesterone (25 mg/kg, bid x 7 days) and then on day 7 were treated with finasteride (50 mg/kg), which causes neurosteroid withdrawal by blocking conversion of progesterone into neurosteroids. Fully hippocampus-kindled mice were utilized to assess the antiseizure sensitivity of neurosteroids during neurosteroid withdrawal. Results: Neurosteroid withdrawal induced a twofold increase in ?-subunit mRNA expression in WT mice, but this upregulation was undiminished in PRKO mice. Neurosteroid withdrawal-induced ?-subunit upregulation was associated with enhanced antiseizure sensitivity of the neurosteroid allopregnanolone and significant reduction in the antiseizure sensitivity of the benzodiazepine diazepam. Conclusions: These results indicate that neurosteroid withdrawal-induces upregulation of GABA-A receptor ?-subunit expression in the hippocampus via a PR-independent signaling pathway. The enhanced neurosteroid sensitivity observed during neurosteroid withdrawal may be due to increase in abundance of ?-containing receptors in the hippocampus. *Supported by NIH grant NS051398*