Specific subunit mRNAs of the GABA_A receptor are regulated by progesterone in subfields of the hippocampus

The ability of ovarian steroids to regulate the excitability of hippocampal neurons may be mediated by alterations in the inhibitory activity of GABA. We assessed the ability of estradiol, progesterone, and 3α-OH-5α-pregnan-20-one (3α-OH-DHP; a metabolite of progesterone) to regulate gene expression of selected GABA_A receptor subunits (α1, α2, β1, β2, and γ2). Using in situ hybridization, we found that progesterone, or 3α-OH-DHP, suppressed mRNA levels for the α1 subunit in the CA2, CA3, and the dentate gyrus subfields of the hippocampus in animals that were pretreated with estradiol. Progesterone had a more limited effect on the α2 subunit, suppressing mRNA levels in estradiol-primed animals only in the CA3 region. In contrast, progesterone increased mRNA levels for the γ2 subunit in the CA1, CA2, and CA3 regions of the hippocampus, but only in animals that were not estradiol-primed. Estradiol alone had no significant effect on the expression of any subunit examined. β1 and β2 subunit mRNA levels were not altered by any of the hormones tested. These data support the conclusion that progesterone and its metabolites may regulate excitability of the hippocampus by modulating the GABA_A receptor gene expression; these effects of progesterone are dependent upon the circulating levels of estradiol. Alterations in the gene expression of selective subunits may lead to changes in the density of GABA_A receptor protein or to changes in receptor subunit composition which might alter receptor sensitivity to activation by GABA or modulators such as the benzodiazepines and convulsants.