GABAA receptors as targets for treating affective and cognitive symptoms of depression.

A neuroactive steroid (NAS) targeting δ-GABA A receptors has been approved for the treatment of peripartum depression; clinical trials of NASs for the treatment of major depressive disorder are ongoing. Preclinical studies indicate that both positive and negative modulators of α5-GABA A receptors (α5-GABA A Rs) have antidepressant-like actions; we discuss a model that explains how bidirectional modulation of the same GABA A receptor population can result in antidepressant-like action. A model for how positive allosteric modulation of α5-GABA A Rs may lead to an improved signal-to-noise ratio in cortical microcircuits and thus restored information processing and cognitive function is discussed. In the past 20 years, our understanding of the pathophysiology of depression has evolved from a focus on an imbalance of monoaminergic neurotransmitters to a multifactorial picture including an improved understanding of the role of glutamatergic excitatory and GABAergic inhibitory neurotransmission. FDA-approved treatments targeting the glutamatergic [esketamine for major depressive disorder (MDD)] and GABAergic (brexanolone for peripartum depression) systems have become available. This review focuses on the GABA A receptor (GABA A R) system as a target for novel antidepressants and discusses the mechanisms by which modulation of δ-containing GABA A Rs with neuroactive steroids (NASs) or of α5-containing GABA A Rs results in antidepressant or antidepressant-like actions and discusses clinical data on NASs. Moreover, a potential mechanism by which α5-GABA A R-positive allosteric modulators (PAMs) may improve cognitive deficits in depression is presented. [ABSTRACT FROM AUTHOR]