Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress

Abstract

Chronic stress is a risk factor for Major depressive disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side effects. This study investigated the activity profiles and behavioral efficacy of two molecules enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and have anti-depressant and pro-cognitive effects independently.Using unpredictable chronic mild stress (UCMS) in male and female mice (n=12/group), we show that acute and chronic administration of GL-RM combined the anti-depressant and pro-cognitive effects of each enantiomer, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.

Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition model of Alzheimer’s disease pathology

“…At 5 months of age, we found GL-II-73 had a dose dependent effect in remedying the cognitive deficit. This is consistent with our previous work showing dose dependent benefits of 10mg/kg over 5mg/kg in the unpredictable chronic mild stress model and aging model 24,29 . Here, the 5 month chronic study also showed spatial working memory deficits reversed by GL-II-73.…”

“…This study was designed to investigate the impact of modulation of α5-GABAA receptors at early and late amyloid deposition to determine functional, morphological and histological effects related to cognition and pathology. This work was driven by observations that SST interneurons and the GABAergic system is affected in AD, and that selective α5 GABA-A-R modulation has pro-cognitive effects in models of stress and aging which are also well documented risk factors for AD 24,29 . In the 5XFAD model of amyloid load, we tested acute and chronic GL-II-73 at 2 months of age and 5 months of age on spatial working memory.…”

“…We showed that the use of an α5-PAM has pro-cognitive properties in stress induced and aging models 24,29 , which are models exhibiting SST deficits. In these models, we also showed that chronic treatment with an α5-PAM can increase dendritic length and spine density, on postsynaptic cells, which altogether suggests a combined symptomatic and disease-modifying effect of the intervention.…”

GABAA receptor subtypes and benzodiazepine use, misuse, and abuse

“…Findings from early studies indeed indicated that BDZ modulation of α1GABAARs is required for the sedative effects ( 14 ), while BDZ modulation of α2GABAARs is required for the anxiolytic-like effects of BDZs ( 15 ). Continued work in this area not only confirmed and further expanded the association of specific behavioral effects with specific GABAAR subtypes ( 16 – 25 ), but uncovered new, previously unappreciated indications for subtype-selective GABAAR modulation ( 26 – 30 ).…”

Abnormal expression of cortical cell cycle regulators underlying anxiety and depressive-like behavior in mice exposed to chronic stress

“…The literature consistently shows that suppression of adult hippocampal neurogenesis caused by stress ( Besnard and Sahay, 2016 ; Drew and Huckleberry, 2017 ; Huckleberry et al, 2018 ) might contribute to a maladaptive emotional and stress-coping strategy. Several lines of evidence have indicated that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces volumetric ( de Lange et al, 2008 ; McEwen et al, 2016 ; Misquitta et al, 2021 ), cytoarchitectural ( Misquitta et al, 2021 ), and morphological changes, including the reduction of dendrite length, branching, and spine density ( McEwen, 1997 ; McEwen and Magarinos, 1997 ; Radley et al, 2006 ; Arnsten, 2009 ; Kang et al, 2012 ; Arnsten et al, 2015 ; Qiao et al, 2016 ; Moreno et al, 2017 ; Banasr et al, 2021 ; Bernardo et al, 2022 ). In addition, altered PFC neuronal activity is associated with social defeat-induced depression- and anxiety-like behavior in mice, and learning and memory impairments ( Sullivan and Gratton, 2002 ; Lupien et al, 2009 ; Felix-Ortiz et al, 2016 ; Burgos-Robles et al, 2017 ; Planchez et al, 2019 ).…”