Neurosteroid Synthesis-Mediated Regulation of GABAAReceptors: Relevance to the Ovarian Cycle and Stress

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Abstract
Recently, we demonstrated cyclic alterations in GABAAreceptor (GABAAR) subunit composition over the ovarian cycle correlated with fluctuations in progesterone levels. However, it remains unclear whether this physiological regulation of GABAARs is directly mediated by hormones. Here, we show that both ovarian and stress hormones are capable of reorganizing GABAARs by actions through neurosteroid metabolites. The cyclic alterations in GABAARs demonstrated in female mice can be mimicked with exogenous progesterone treatment in males or in ovariectomized females. Progesterone (5 mg/kg, twice daily) upregulates the expression of GABAAR δ subunits and enhances the tonic inhibition mediated by these receptors in dentate gyrus granule cells (DGGCs). These changes in males as well as ovarian cycle-induced changes in females can be blocked by finasteride, an antagonist of neurosteroid synthesis from progesterone. The altered GABAAR expression is unaffected by the progesterone receptor antagonist RU486 [mifepristone (11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], suggesting that neurosteroid synthesis and not progesterone receptor activation underlies the hormone-mediated effects on GABAAR expression. Neurosteroids can alter GABAAR expression on a rapid timescale, because GABAAR upregulation can be induced in brain slices maintainedin vitroafter a short (30 min) treatment with the neurosteroid 3α,5α-tetrahydrodeoxycorticosterone (THDOC) (100 nm). Consistent with these rapid alterations, acute stress, a condition known to quickly raise THDOC levels, within 30 min induces upregulation of GABAAR δ subunit expression and increase tonic inhibition in DGGCs. These results reveal that several physiological conditions characterized by elevations in neurosteroid levels induce a reorganization of GABAARs through the action of neurosteroids.