Weiland N G, Orchinik M
Laboratory of Neuroendocrinology, Rockefeller University, New York, NY 10021, USA.
Brain Res Mol Brain Res. 1995 Sep;32(2):271-8. doi: 10.1016/0169-328x(95)00087-9.
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 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha-OH-DHP; a metabolite of progesterone) to regulate gene expression of selected GABAA receptor subunits (alpha 1, alpha 2, beta 1, beta 2, and gamma 2). Using in situ hybridization, we found that progesterone, or 3 alpha-OH-DHP, suppressed mRNA levels for the alpha 1 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 alpha 2 subunit, suppressing mRNA levels in estradiol-primed animals only in the CA3 region. In contrast, progesterone increased mRNA levels for the gamma 2 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. Beta 1 and beta 2 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 GABAA 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 GABAA 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.
卵巢甾体调节海马神经元兴奋性的能力可能是由γ-氨基丁酸（GABA）抑制活性的改变介导的。我们评估了雌二醇、孕酮和3α-羟基-5α-孕烷-20-酮（3α-OH-DHP；孕酮的一种代谢产物）调节所选GABAA受体亚基（α1、α2、β1、β2和γ2）基因表达的能力。通过原位杂交，我们发现，在预先用雌二醇处理的动物中，孕酮或3α-OH-DHP可抑制海马CA2、CA3和齿状回亚区中α1亚基的mRNA水平。孕酮对α2亚基的影响较为有限，仅在CA3区抑制了经雌二醇预处理动物的mRNA水平。相比之下，孕酮可增加海马CA1、CA2和CA3区γ2亚基的mRNA水平，但仅在未用雌二醇预处理的动物中出现这种情况。单独使用雌二醇对所检测的任何亚基的表达均无显著影响。β1和β2亚基的mRNA水平未因所测试的任何激素而改变。这些数据支持以下结论：孕酮及其代谢产物可能通过调节GABAA受体基因表达来调节海马的兴奋性；孕酮的这些作用取决于雌二醇的循环水平。选择性亚基基因表达的改变可能导致GABAA受体蛋白密度的变化或受体亚基组成的变化，这可能会改变受体对GABA或诸如苯二氮䓬类药物和惊厥剂等调节剂激活的敏感性。
