Abstracts

Many women with epilepsy experience cycle-related increased seizure susceptibility, correlated with low progesterone levels, termed catamenial epilepsy. Progesterone metabolites are known to be potent modulators of GABA[sub]A[/sub] receptors (GABA[sub]A[/sub]Rs) and tonic inhibition mediated by [delta] subunit-containing GABA[sub]A[/sub]Rs is an important site of action of neurosteroids. Recurring fluctuations in the levels of neurosteroids are prime candidates for mediating changes in neuronal excitability over the ovarian cycle, but the precise mechanisms responsible for their actions have yet to be elucidated. We hypothesize that endogenous neurosteroids dynamically reorganize GABA[sub]A[/sub]Rs, leading to longer-term changes in GABAergic synaptic transmission, neuronal excitability, and seizure predisposition. GABA[sub]A[/sub]R subunit expression, GABA[sub]A[/sub]R function, seizure susceptibility, and anxiety were compared in mice at two diametrically opposed stages of the estrous cycle with very different hormonal profiles: the estrus phase when estrogen levels are high and progesterone levels are low and the diestrus phase when estrogen levels are low and progesterone levels are high. GABA[sub]A[/sub]R subunit expression was analyzed by Western blot analysis and GABA[sub]A[/sub]R function was analyzed by whole-cell patch clamp recording. Neuronal excitability was analyzed by measuring seizure susceptibility by hippocampal depth electroencephalogram (EEG) recording and anxiety levels using the elevated plus maze. Here we demonstrate cyclic changes in GABA[sub]A[/sub]R subunit expression over the estrous cycle result in cyclic changes in tonic GABAergic inhibition, accompanied by fluctuations in seizure susceptibility and anxiety. When circulating progesterone levels are elevated in diestrus, GABA[sub]A[/sub]R [delta] subunit expression and GABA[sub]A[/sub]R [delta] subunit-mediated tonic inhibition in dentate gyrus granule cells (DGGCs) are increased associated with decreased seizure susceptibility and anxiety. Blocking the cyclic increase in GABA[sub]A[/sub]R [delta] subunit expression at late diestrus, using GABA[sub]A[/sub]R [delta] subunit antisense mRNA or using GABA[sub]A[/sub]R [delta]^-/- or [delta]^+/- mice, prevents the decreased seizure susceptibility and anxiety levels during diestrus. Our data demonstrate that there are normal regulatory mechanisms controlling expression of GABA[sub]A[/sub]Rs structure and function over the ovarian cycle, which play a role in controlling neuronal excitability. Dysfunction in these normal regulatory processes may be defective in cyclic-associated neurological disorders, such as catamenial epilepsy or premenstrual dysphoric disorder (PMDD). (Supported by NIH Grants NS30549, NS02808, and the [italic]Coelho Endowment[/italic] to I.M. J.M was also supported by the Training Program in Neural Repair (T32 NS07449).)