Article abstract
Nature Neuroscience 10, 469 - 477 (2007)
Published online: 11 March 2007 | doi:10.1038/nn1868
Reversal of neurosteroid effects at 
4
2
GABAA receptors triggers anxiety at puberty
Hui Shen1, Qi Hua Gong1, Chiye Aoki2, Maoli Yuan1, Yevgeniy Ruderman1, Michael Dattilo1, Keith Williams1 & Sheryl S Smith1
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 
4
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 42 receptors, and this effect depends on arginine 353 in the 4 subunit, a putative site for modulation by Cl-. Therefore, inhibition of 42 GABAA receptors by THP provides a mechanism for the generation of anxiety at puberty.
- Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.
- Center for Neural Science, New York University, 6 Washington Place, New York, New York 10003, USA.
Correspondence to: Sheryl S Smith1 e-mail: sheryl.smith@downstate.edu
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