title: Neurosteroid effects at α4βδ GABAA receptors alter spatial learning and synaptic plasticity in CA1 hippocampus across the estrous cycle of the mouse.
abstract: Fluctuations in circulating levels of ovarian hormones have been shown to regulate cognition (Sherwin and Grigorova, 2011. Fertil. Steril. 96, 399-403; Shumaker et al., 2004. JAMA. 291, 2947-2958), but increases in estradiol on the day of proestrus yield diverse outcomes: In vivo induction of long-term potentiation (LTP), a model of learning, is reduced in the morning, but optimal in the afternoon (Warren et al., 1995. Brain Res. 703, 26-30). The mechanism underlying this discrepancy is not known. Here, we show that impairments in both CA1 hippocampal LTP and spatial learning observed on the morning of proestrus are due to increased dendritic expression of α4βδ GABAA receptors (GABARs) on CA1 pyramidal cells, as assessed by electron microscopic (EM) techniques, compared with estrus and diestrus. LTP induction and spatial learning were robust, however, when assessed on the morning of proestrus in α4-/- mice, implicating these receptors in mediating impaired plasticity. Although α4βδ expression remained elevated on the afternoon of proestrus, increases in 3α-OH-THP (3α-OH-5α-pregnan-20-one) decreased inhibition by reducing outward current through α4βδ GABARs (Shen et al., 2007. Nat. Neurosci. 10, 469-477), in contrast to the usual effect of this steroid to enhance inhibition. Proestrous levels of 3α-OH-THP reversed the deficits in LTP and spatial learning, an effect prevented by the inactive metabolite 3β-OH-THP (10 mg/kg, i.p.), which antagonizes actions of 3α-OH-THP. In contrast, administration of 3α-OH-THP (10 mg/kg, i.p.) on the morning of proestrus improved spatial learning scores 150-300%. These findings suggest that cyclic fluctuations in ovarian steroids can induce changes in cognition via α4βδ GABARs that are dependent upon 3α-OH-THP. This article is part of a Special Issue entitled SI: Brain and Memory.
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA; Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Sabaliauskas
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA; School of Biomedical Engineering, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA.
authors.forename: Jonela
authors.initials: J
authors.lastname: Molla
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA.
authors.forename: Qi Hua
authors.initials: QH
authors.lastname: Gong
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA.
authors.forename: Aarti
authors.initials: A
authors.lastname: Kuver
authors.affiliation: Center for Neural Science, New York University, 4 Washington Place, New York, NY 10003, USA.
authors.forename: Chiye
authors.initials: C
authors.lastname: Aoki
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203, USA; The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. Electronic address: sheryl.smith@downstate.edu.
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Smith
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D004558:Electric Stimulation; D004958:Estradiol / Q000008:administration & dosage / Q000502:physiology*; D030762:Estrous Cycle; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011280:Pregnanolone / Q000031:analogs & derivatives / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; C053623:pregnane-20-one; D004958:Estradiol; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone
keywords: Allopregnanolone; Alpha4; Cognition; Delta; GABA-A receptor; Ovarian hormones