Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by δ subunit–containing GABAA receptors (δGABAARs). Here we demonstrate periodic alterations in specific GABAAR subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of δGABAARs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAARs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of δGABAARs in individuals with catamenial epilepsy or PMDD.
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We thank W. Sieghart (University of Vienna) for the gift of some of the antibodies used in this study. This work was supported by US National Institutes of Health grants NS30549 and NS02808 and by the Coelho Endowment to I.M. J.M was also supported by the Training Program in Neural Repair (T32 NS07449).
The authors declare no competing financial interests.
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Maguire, J., Stell, B., Rafizadeh, M. et al. Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci 8, 797–804 (2005). https://doi.org/10.1038/nn1469
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