title: PR-independent neurosteroid regulation of α2-GABA-A receptors in the hippocampus subfields.
abstract: Progesterone (P) binding to the intracellular progesterone receptors (PRs) plays a key role in epilepsy via modulation of GABA-A receptor plasticity in the brain. This is thought to occur via conversion of P to neurosteroids such as allopregnanolone, an allosteric modulator of GABA-A receptors. In the female brain, the composition of GABA-A receptors is not static and undergoes dynamic spatial changes in response to fluctuations in P and neurosteroid levels. Synaptic α2-containing GABA-A receptors contribute to phasic neuronal excitability and seizure susceptibility. However, the mechanisms underlying α2-subunit plasticity remain unclear. Here, we utilized the neurosteroid synthesis inhibitor finasteride and PR knockout mice to investigate the role of PRs in α2-subunit in the hippocampus. α2-Subunit expression was significantly upregulated during the high-P state of diestrous stage and with P treatment in wildtype and PR knockout mice. In contrast, there was no change in α2-subunit expression when metabolism of P into neurosteroids was blocked by finasteride in both genotypes. These findings suggest that ovarian cycle-related P and neurosteroids regulate α2-GABA-A receptor expression in the hippocampus via a non-PR pathway, which may be relevant to menstrual-cycle related brain conditions.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA. Electronic address: reddy@medicine.tamhsc.edu.
authors.forename: Doodipala Samba
authors.initials: DS
authors.lastname: Reddy
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA.
authors.forename: Omkaram
authors.initials: O
authors.lastname: Gangisetty
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, TX 77807, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D004031:Diestrus / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: C493920:Gabra2 protein, mouse; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011980:Receptors, Progesterone; D011374:Progesterone
keywords: Epilepsy; GABA receptor; Neurosteroid; Perimenstrual; Progesterone; α2-Subunit