Nature Neuroscience8, 797 - 804 (2005)
Published online: 15 May 2005; | doi:10.1038/nn1469
Ovarian cycle−linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety
Jamie L Maguire, Brandon M Stell, Mahsan Rafizadeh
& Istvan Mody
Departments of Neurology and Physiology, The David Geffen School of Medicine, University of California Los Angeles, 710 Westwood Plaza, Los Angeles, California 90095, USA.
Correspondence should be addressed to Istvan Mody mody@ucla.edu
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 subunit−containing GABAA receptors (GABAARs). 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 GABAARs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of GABAARs 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 GABAARs in individuals with catamenial epilepsy or PMDD.
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