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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 α2- and 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 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 separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, 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.

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Fig. 1: Electrophysiological, pharmacokinetic and behavioral profiles of GL-II-73 and GL-I-54.
Fig. 2: Effect of acute treatment of GL-RM on anxiety, emotionality and working memory deficits in mice subjected to chronic stress.
Fig. 3: Effect of chronic treatment of GL-RM on anxiety, emotionality and working memory deficits in mice subjected to chronic stress.
Fig. 4: Chronic treatment with GL-RM reverses chronic-stress induced spine density reduction in the PFC and the CA1.

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Acknowledgements

Authors thank Mehrab Ali and Netta Ussyshkin for support with administrative tasks throughout the study. They thank CAMH animal facility staff for the caring for our animals over the study duration. Authors further thank the members from Charles River Laboratories and NeuroDigitech for their contribution to data generation. We also thank Milwaukee Institute for Drug Discovery and University of Wisconsin-Milwaukee’s Shimadzu Laboratory for Advanced and Applied Analytical Chemistry for help with spectroscopy and National Science Foundation, Division of Chemistry [CHE-1625735].

Funding

CAMH Internal Fund (Discovery Fund), awarded to TP at the time of study execution, and the Campbell Family Mental Health Research Institute of CAMH. Chemistry synthesis funded by NIH (DA-043204, R01NS076517) to JMC. The Science Fund of the Republic of Serbia funded the pharmacokinetic study through Grant No. 7749108 NanoCellEmoCog. JMC, MMS, ES and TP are listed inventors on patents covering syntheses and use of the compounds. ES is Founder of Damona Pharmaceuticals, a biopharma dedicated to bring novel GABAergic compounds to the clinic. AB, PL, MM, MYM, SR, DS, and AK report no conflict of interest.

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TP and ES designed the study. MYM, SR, DS and JMC synthesized the compounds tested in this study. TP and PL performed the behavioral piece. AK and MMS performed the pharmacokinetic piece. Electrophysiology was outsourced to Charles River Laboratories. TP, AB and MM analyzed the data. TP and AB wrote the manuscript.

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Correspondence to Etienne Sibille or Thomas D. Prevot.

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Bernardo, A., Lee, P., Marcotte, M. et al. Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress. Neuropsychopharmacol. 47, 1608–1619 (2022). https://doi.org/10.1038/s41386-022-01360-y

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