α2-containing γ-aminobutyric acid type A receptors promote stress resiliency in male mice

Brain α2-containing GABA_A receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of α2-containing GABA_A receptors following chronic social defeat stress using male mice deficient in the α2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the α2 subunit on intermediates of the glutathione synthesis pathway. We found that α2-containing GABA_A receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of α2-containing GABA_A receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light–dark box, and novel open field tests. Increases in indices of oxidative stress—reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios—were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking α2-containing GABA_A receptors. We conclude that α2-containing GABA_A receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that α2-containing GABA_A receptors provide against oxidative stress in NAc and the prefrontal cortex.