Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress.

Recently, we demonstrated cyclic alterations in GABA(A) receptor (GABA(A)R) subunit composition over the ovarian cycle correlated with fluctuations in progesterone levels. However, it remains unclear whether this physiological regulation of GABA(A)Rs is directly mediated by hormones. Here, we show that both ovarian and stress hormones are capable of reorganizing GABA(A)Rs by actions through neurosteroid metabolites. The cyclic alterations in GABA(A)Rs 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 GABA(A)R delta 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 GABA(A)R expression is unaffected by the progesterone receptor antagonist RU486 [mifepristone (11beta-[p-(dimethylamino)phenyl]-17beta-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 GABA(A)R expression. Neurosteroids can alter GABA(A)R expression on a rapid timescale, because GABA(A)R upregulation can be induced in brain slices maintained in vitro after a short (30 min) treatment with the neurosteroid 3alpha,5alpha-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 GABA(A)R delta 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 GABA(A)Rs through the action of neurosteroids.