Neurosteroid withdrawal regulates GABA-A receptor 4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway.
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Neurosteroids regulate GABA-A receptor plasticity. Neurosteroid withdrawal occurs during menstruation and is associated with a marked increase in expression of GABA-A receptor 4-subunit, a key subunit linked to enhanced neuronal excitability, seizure susceptibility and benzodiazepine resistance. However, the molecular mechanisms underlying the upregulation of 4-subunit expression remain unclear. Here we utilized the progesterone receptor (PR) knockout mouse to investigate molecular pathways of PR and the transcription factor early growth response factor-3 (Egr3) in regulation of the GABA-A receptor 4-subunit expression in the hippocampus in a mouse neurosteroid withdrawal paradigm. Neurosteroid withdrawal induced a threefold increase in 4-subunit expression in wild-type mice, but this upregulation was unchanged in PR knockout mice. The expression of Egr3, which controls 4-subunit transcription, was increased significantly following neurosteroid withdrawal in wild-type and PR knockout mice. Neurosteroid withdrawal-induced 4-subunit upregulation was completely suppressed by antisense Egr3 inhibition. In the hippocampus kindling model of epilepsy, there was heightened seizure activity, significant reduction in the antiseizure sensitivity of diazepam (a benzodiazepine insensitive at 4-receptors) and conferral of increased seizure protection of flumazenil (a low-affinity agonist at 4-receptors) in neurosteroid-withdrawn wild-type and PR knockout mice. These observations are consistent with enhanced 4-containing receptor abundance in vivo. Neurosteroid withdrawal-induced seizure exacerbation, diazepam insensitivity, and flumazenil efficacy in the kindling model were reversed by inhibition of Egr3. These results indicate that neurosteroid withdrawal-induced upregulation of GABA-A receptor 4-subunit expression is mediated by the Egr3 via a PR-independent signaling pathway. These findings help advance our understanding of the molecular basis of catamenial epilepsy, a neuroendocrine condition that occurs around the perimenstrual period and is characterized by neurosteroid withdrawal-linked seizure exacerbations in women with epilepsy.
