Reversal of neurosteroid effects at α4β2δ 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 α4βδ GABA_A 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 α4β2δ receptors, and this effect depends on arginine 353 in the α4 subunit, a putative site for modulation by Cl⁻. Therefore, inhibition of α4β2δ GABA_A receptors by THP provides a mechanism for the generation of anxiety at puberty.