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 GABA(A) receptors, which are functionally defined by their a subunit (alpha 1-alpha 6). Although it remains unknown which specific GABA(A) receptor population mediates depressive-like effects, we posit that ea-containing GABA(A) receptors, which are highly expressed in limbic regions, may underlie these behaviors. We hypothesized that genetic inactivation of alpha 2-containing GABA(A) receptors would generate a depressive-like phenotype in mice. Male and female wild type, alpha 2 heterozygous, and alpha 2 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 alpha 2 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 alpha 2-containing GABA(A) receptors has an antidepressant-like effect in vivo and that these receptors represent a specific molecular substrate that can regulate depressive-like states. alpha 2-containing GABA(A) receptors may therefore represent a novel target for the development of more effective antidepressants. (C) 2010 Elsevier B.V. All rights reserved.