title: Estrous cycle regulation of extrasynaptic δ-containing GABA(A) receptor-mediated tonic inhibition and limbic epileptogenesis.
abstract: The ovarian cycle affects susceptibility to behavioral and neurologic conditions. The molecular mechanisms underlying these changes are poorly understood. Deficits in cyclical fluctuations in steroid hormones and receptor plasticity play a central role in physiologic and pathophysiologic menstrual conditions. It has been suggested that synaptic GABA(A) receptors mediate phasic inhibition in the hippocampus and extrasynaptic receptors mediate tonic inhibition in the dentate gyrus. Here we report a novel role of extrasynaptic δ-containing GABA(A) receptors as crucial mediators of the estrous cycle-related changes in neuronal excitability in mice, with hippocampus subfield specificity. In molecular and immunofluorescence studies, a significant increase occurred in δ-subunit, but not α4- and γ2-subunits, in the dentate gyrus during diestrus. However, δ-subunit upregulation was not evident in the CA1 region. The δ-subunit expression was undiminished by age and ovariectomy and in mice lacking progesterone receptors, but it was significantly reduced by finasteride, a neurosteroid synthesis inhibitor. Electrophysiologic studies confirmed greater potentiation of GABA currents by progesterone-derived neurosteroid allopregnanolone in dissociated dentate gyrus granule cells in diestrus than in CA1 pyramidal cells. The baseline conductance and allopregnanolone potentiation of tonic currents in dentate granule cells from hippocampal slices were higher than in CA1 pyramidal cells. In behavioral studies, susceptibility to hippocampus kindling epileptogenesis was lower in mice during diestrus. These results demonstrate the estrous cycle-related plasticity of neurosteroid-sensitive, δ-containing GABA(A) receptors that mediate tonic inhibition and seizure susceptibility. These findings may provide novel insight on molecular cascades of menstrual disorders like catamenial epilepsy, premenstrual syndrome, and migraine.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807-3260, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Omkaram
authors.initials: O
authors.lastname: Gangisetty
authors.forename: Chase Matthew
authors.initials: CM
authors.lastname: Carver
authors.forename: Doodipala Samba
authors.initials: DS
authors.lastname: Reddy
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004198:Disease Susceptibility; D004827:Epilepsy / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D030762:Estrous Cycle; D005260:Female; D059330:GABAergic Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007696:Kindling, Neurologic; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects; D009473:Neuronal Plasticity; D011280:Pregnanolone / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; C583130:Gabrd protein, mouse; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011980:Receptors, Progesterone; D011374:Progesterone; D011280:Pregnanolone