Reversal of neurosteroid effects at alpha4beta2delta GABAA receptors triggers anxiety at puberty.
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.
Shen
Hui
H
Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.
Gong
Qi Hua
QH
Aoki
Chiye
C
Yuan
Maoli
M
Ruderman
Yevgeniy
Y
Dattilo
Michael
M
Williams
Keith
K
Smith
Sheryl S
SS
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
D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001120:Arginine; D011280:Pregnanolone