Sex-Dependent Anti-Stress Effect of an α5 Subunit Containing GABAA Receptor Positive Allosteric Modulator

Abstract

Rationale: Current first-line treatments for stress-related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells.Objectives: The present study evaluates whether SH-053-2’F-R-CH3 (denoted “α5-PAM”), a positive allosteric modulator selective for α5-subunit containing GABAA receptors found predominantly on cortical pyramidal cell dendrites, has anti-stress effects.Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with α5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally.Results: Acute and chronic α5-PAM treatments produce a pattern of decreased stress-induced behaviors (denoted as “behavioral emotionality”) across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic α5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to α5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with α5-PAM in females only, and these expression changes correlated with behavioral emotionality.Conclusion: We showed that acute and chronic positive modulation of α5 subunit-containing GABAA receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.

Sex-Specific Effects of Stress on Mood-Related Gene Expression

“…The Gabra5 gene has SNPs with an association for suicide, but human postmortem brain studies report mixed results for changes in expression in subjects committing suicide and/or with MDD (increased expression in BA20 and BA46 [85], but no change in the amygdala [88]). Interestingly, we previously found that treating mice with a positive allosteric modulator for the α5 subunit of the GABA receptor (the subunit coded for by the Gabra5 gene) decreased measures of anxiety-/depressive-like behaviors in female mice but not in male mice [89]. Here, we find that chronic stress decreased Gabra5 expression in the PFC and NAc of both males and females.…”

Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex

“…The only cross-species difference was found in SST cells: wherein Gabra5 was absent in mouse SST cells, a small proportion of human SST cells expressed GABRA5 (8%). Given that recent studies investigating the therapeutic potential of modulating α5-GABA A Rs have shown promise in preclinical models of mood disorders [18, 27-30], our findings may be useful for understanding the potential influence of α5-GABA A R-selective pharmacological agents on cortical microcircuit activity at the cellular and network levels.…”

“…SST cell inhibition primarily targets PYC dendrites, gating the input of excitatory signals from thalamocortical afferents or upstream microcircuitry, a function that is partially mediated by activation of dendritic α5 subunit-containing GABA subtype A receptors (α5-GABA A Rs) [16, 17]. Thus, enhancing (or modulating) signaling specifically at α5-GABA A Rs provides a potential means to restore, or overcome, the low SST cell function found in MDD [18]. Indeed, a growing number of experimental manipulations in rodents suggest that remediating low SST cell function may lead to antidepressant-like effects (see review in Fee et al [19]).…”

Novel Benzodiazepine-Like Ligands with Various Anxiolytic, Antidepressant, or Pro-Cognitive Profiles

“…The BZ anxiolytic properties are mediated predominantly by α2-GABAA-Rs [16] and also by α5-GABAA-Rs [17, 18]. Selective activity at α5-GABAA-Rs has also been suggested to play a critical role in alleviating “behavioral emotionality” (anxiety and depressive-like behaviors) in a mouse model of depression (using chronic stress in mice [19]) or cognitive dysfunctions in mouse models of schizophrenia [20] or in old rats [21]. The α5-GABAA-Rs have predominant distribution in the neocortex and hippocampus [22] suggesting a role in cognition and emotion [17, 23], while α1-GABAA-Rs have ubiquitous distribution and are very abundant [24], potentially explaining their effect on sedation [25] and their controversial role in cognition [15, 26].…”