The influence of stress at puberty on mood and learning: role of the α4βδ GABAA receptor

Neuroscience. 2013 Sep 26;249:192-213. doi: 10.1016/j.neuroscience.2012.09.065. Epub 2012 Oct 16.


It is well-known that the onset of puberty is associated with changes in mood as well as cognition. Stress can have an impact on these outcomes, which in many cases, can be more influential in females, suggesting that gender differences exist. The adolescent period is a vulnerable time for the onset of certain psychopathologies, including anxiety disorders, depression and eating disorders, which are also more prevalent in females. One factor which may contribute to stress-triggered anxiety at puberty is the GABAA receptor (GABAR), which is known to play a pivotal role in anxiety. Expression of α4βδ GABARs increases on the dendrites of CA1 pyramidal cells at the onset of puberty in the hippocampus, part of the limbic circuitry which governs emotion. This receptor is a sensitive target for the stress steroid 3α-OH-5[α]β-pregnan-20-one or [allo]pregnanolone, which paradoxically reduces inhibition and increases anxiety during the pubertal period (post-natal day ∼35-44) of female mice in contrast to its usual effect to enhance inhibition and reduce anxiety. Spatial learning and synaptic plasticity are also adversely impacted at puberty, likely a result of increased expression of α4βδ GABARs on the dendritic spines of CA1 hippocampal pyramidal cells, which are essential for consolidation of memory. This review will focus on the role of these receptors in mediating behavioral changes at puberty. Stress-mediated changes in mood and cognition in early adolescence may have relevance for the expression of psychopathologies in adulthood.

Keywords: 17β-estradiol (an estrogen); 3α,21-dihydroxy-5α-pregnan-20-one; 3α-HSD; 3α-OH-5[α]β-pregnan-20-one or [allo]pregnanolone; 3α-hydroxysteroid oxidoreductase; ABA; BDNF; CRH; DHEA; DHEAS; E(2); EPSC/EPSP; ER; GABA(A) receptor; GABA-A receptor; GABAR; K(+)-Cl(−) co-transporter; KCC2; LTP; N-methyl-d-aspartate; NKCC1; NMDA; Na(+)-K(+)-Cl(−) co-transporter; P; PMDD; PND; PVN; SIG; T; TBS; TEA; THDOC; THP; TTX; activity-based animal model of anorexia nervosa; alpha4; anxiety; brain-derived neurotrophic factor; cognition; corticotrophin-releasing hormone; dehydroepiandrosterone; dehydroepiandrosterone sulfate; delta; estrogen receptor; excitatory post-synaptic current/potential; fMRI; functional magnetic resonance imaging; long-term potentiation; paraventricular nucleus (hypothalamus); post-natal day; premenstrual dysphoric disorder; progesterone; puberty; silver-intensified gold; testosterone; tetra-ethylammonium; tetrodotoxin; theta-burst stimulation.

Publication types

  • Review

MeSH terms

  • Affect / physiology*
  • Animals
  • Emotions / physiology
  • Humans
  • Learning / physiology*
  • Puberty / physiology*
  • Receptors, GABA-A / physiology*
  • Stress, Psychological / metabolism*
  • Stress, Psychological / psychology


  • GABRA4 protein, human
  • GABRB1 protein, human
  • GABRD protein, human
  • Receptors, GABA-A