Those Anxious Adolescents

Abstract

Why are teenagers so prone to moodiness and melodrama? Research by Shen et al . on mice suggests that neurosteroids, which potentiate γ-aminobutyric acid (GABA)-mediated chloride conductance and are antianxiety agents in adults, actually act to promote excitability and stimulate anxiety during puberty. Shen et al . found that the neurosteroid known as THP (3α-OH-5α[β]-pregnan-20-one) decreased, rather than increased, chloride conductance through a specific GABA receptor composed of α4β2δ subunits when this receptor was expressed in human embryonic kidney (HEK) 293 cells. In female mice, the abundance of the α4 and δ subunits, which were determined as critical for this reversed effect of THP, increased at the onset of puberty, whereas these subunits were barely detectable in prepubertal and adult animals. Electrophysiological recordings of hippocampal slices of pubertal mice confirmed that THP reduced GABA-mediated tonic inhibitory current and increased neuronal excitability, which is consistent with these GABA receptors serving as extrasynaptic tonic inhibitors of neural activity. In contrast, THP increased tonic current and neuronal excitability before puberty or in mice in which the δ subunit was knocked out. In vivo, administration of THP to pubertal mice or induction of stress, which raises endogenous production of THP, increased anxiety, measured as a reduction in the time spent in the open arm of an elevated maze. This was in contrast to the behavior of prepubertal and adult mice in which THP increased time spent in the open arm, representing an anxiolytic effect. Inhibition of THP production prevented the pro- or antianxiety effects of previous exposure to stress, thus confirming that in adults and adolescents THP is produced in response to stress despite causing opposite behavioral responses. In adult animals, withdrawal of THP stimulates the appearance of α4 and δ subunits. At the onset of puberty, THP declined, and administration of THP to the pubertal mice prevented the increase in α4 and δ subunits, thus confirming that THP also controls GABA receptor composition in both adult and adolescent mice. Thus, THP appears to be one of the keys to controlling anxiety and understanding adolescent behavior. The implications of this research for teenagers are discussed by McCarthy. H. Shen, Q. H. Gong, C. Aoki, M. Yuan, Y. Ruderman, M. Dattilo, K. Williams, S. S. Smith, Reversal of neurosteroid effects at α4β2δ GABA A receptors triggers anxiety at puberty. Nat. Neurosci. 10 , 469-477 (2007). [PubMed] M. M. McCarthy, GABA receptors make teens resistant to input. Nat. Neurosci. 10 , 397-399 (2007). [PubMed]