title: Reversal of neurosteroid effects at alpha4beta2delta GABAA receptors triggers anxiety at puberty.
abstract: Puberty is characterized by mood swings and anxiety, which are often produced by stress. Here we show that THP (allopregnanolone), a steroid that is released as a result of stress, increases anxiety in pubertal female mice, in contrast to its anxiety-reducing effect in adults. Anxiety is regulated by GABAergic inhibition in limbic circuits. Although this inhibition is increased by THP administration before puberty and in adults, during puberty THP reduces the tonic inhibition of pyramidal cells in hippocampal region CA1, leading to increased excitability. This paradoxical effect of THP results from inhibition of alpha4betadelta GABAA receptors. These receptors are normally expressed at very low levels, but at puberty, their expression is increased in hippocampal area CA1, where they generate outward currents. THP also decreases the outward current at recombinant alpha4beta2delta receptors, and this effect depends on arginine 353 in the alpha4 subunit, a putative site for modulation by Cl-. Therefore, inhibition of alpha4beta2delta GABAA receptors by THP provides a mechanism for the generation of anxiety at puberty.
authors.affiliation: Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Qi Hua
authors.initials: QH
authors.lastname: Gong
authors.forename: Chiye
authors.initials: C
authors.lastname: Aoki
authors.forename: Maoli
authors.initials: M
authors.lastname: Yuan
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Ruderman
authors.forename: Michael
authors.initials: M
authors.lastname: Dattilo
authors.forename: Keith
authors.initials: K
authors.lastname: Williams
authors.forename: Sheryl S
authors.initials: SS
authors.lastname: Smith
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced* / Q000209:etiology*; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D004347:Drug Interactions; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011280:Pregnanolone / Q000378:metabolism / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000648:ultrastructure; D011863:Radioimmunoassay / Q000379:methods; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001120:Arginine; D011280:Pregnanolone