Article abstract

Nature Neuroscience 10, 469 - 477 (2007)
Published online: 11 March 2007 | doi:10.1038/nn1868

Reversal of neurosteroid effects at alpha4bold beta2delta GABAA receptors triggers anxiety at puberty

Hui Shen1, Qi Hua Gong1, Chiye Aoki2, Maoli Yuan1, Yevgeniy Ruderman1, Michael Dattilo1, Keith Williams1 & Sheryl S Smith1

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.

  1. Department of Physiology and Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.
  2. Center for Neural Science, New York University, 6 Washington Place, New York, New York 10003, USA.

Correspondence to: Sheryl S Smith1 e-mail:


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