Abstract
The GABAergic deficit hypothesis of depression states that a deficit of GABAergic transmission in defined neural circuits is causal for depression. Conversely, an enhancement of GABA transmission, including that triggered by selective serotonin reuptake inhibitors or ketamine, has antidepressant effects. Brexanolone, an intravenous formulation of the endogenous neurosteroid allopregnanolone, showed clinically significant antidepressant activity in postpartum depression. By allosterically enhancing GABA A receptor function, the antidepressant activity of allopregnanolone is attributed to an increase in GABAergic inhibition. In addition, allopregnanolone may stabilize normal mood by decreasing the activity of stress-responsive dentate granule cells and thereby sustain resilience behavior. Therefore, allopregnanolone may augment and extend its antidepressant activity by fostering resilience. The recent structural resolution of the neurosteroid binding domain of GABA A receptors will expedite the development of more selective ligands as a potential new class of central nervous system drugs.
Highlights
Major depressive disorder (MDD) represents the most common cause of total psychophysiological disability with a worldwide lifetime prevalence of 12 to 20% and estimated annual costs to the US economy of more than $100 billion[1,2,3]
We summarize the GABAergic deficit hypothesis of depression and its clinical support by the neurosteroid brexanolone, which largely acts by enhancing GABAergic inhibition
Knockout mice that were rendered heterozygous for the γ2 subunit (γ2+/− mice, lacking one of 38 gene alleles that contribute to heteropentameric GABAA receptors) exhibit anxiety- and depression-related behavior, defects in hippocampal neurogenesis, cognitive deficits in emotional pattern separation, and chronic hypothalamic–pituitary– adrenal (HPA) axis activation that are expected of an animal model of MDD23,37–40
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Any comments on the article can be found at the end of the article
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
