Antidepressant-like properties of α2-containing GABAA receptors

Growing evidence suggests that altered function of the GABAergic system can contribute to the pathophysiology of depression. Many GABAergic effects are mediated via ionotropic GABAA receptors, which are functionally defined by their α subunit (α1–α6). Although it remains unknown which specific GABAA receptor population mediates depressive-like effects, we posit that α2-containing GABAA receptors, which are highly expressed in limbic regions, may underlie these behaviors. We hypothesized that genetic inactivation of α2-containing GABAA receptors would generate a depressive-like phenotype in mice. Male and female wild type, α2 heterozygous, and α2 homozygous knockout mice generated on the 129X1/SvJ background were examined in the novelty-suppressed feeding (NSF) test, the forced swim test (FST) and the tail suspension test (TST). Male α2 knockout mice took longer to eat in the NSF test and became immobile faster and remained immobile longer when challenged in the FST and the TST compared to wild types. In females significant genotypic differences were only observed in the FST. We conclude that GABAergic inhibition acting via α2-containing GABAA receptors has an antidepressant-like effect in vivo and that these receptors represent a specific molecular substrate that can regulate depressive-like states. α2-containing GABAA receptors may therefore represent a novel target for the development of more effective antidepressants.

Research highlights▶ α2-containing GABAA receptors are involved in the regulation of mood ▶ Mice lacking α2-containing GABAA receptors exhibit a depressive-like phenotype ▶ GABAergic inhibition acting via α2-containing GABAA receptors has an antidepressant-like effect in vivo.