Introduction: Deficits in somatostatin-positive gamma-aminobutyric acid interneurons (SST+ cells) are associated with major depressive disorder (MDD) and a causal link between SST+ cell dysfunction and depressive-like deficits has been proposed, based on rodent studies showing that chronic stress induces a low SST+ GABA cellular phenotype across corticolimbic brain regions, that lowering Sst, SST+ cell, or GABA functions induces depressive-like behaviors, and that disinhibiting SST+ cell functions has antidepressant effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions with alpha5-GABA-A receptor positive allosteric modulators (alpha5-PAMs) achieved antidepressant-like effects. Together, evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in MDD and that rescuing SST+ cell function may represent a promising therapeutic strategy. Methods: We developed a mouse model with chemogenetic silencing of brain-wide SST+ cells and employed behavioral characterization 30 min after acute or sub-chronic silencing to identify contributions to behaviors related to MDD. We then assessed whether an alpha5-PAM, GL-II-73, could rescue behavioral deficits induced by SST+ cell silencing. Results: Brain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant-like improvements among all behavioral deficits induced by brain-wide SST+ cell silencing. Conclusion: Our data validate SST+ cells as regulators of mood and cognitive functions, support a role for SST+ cell deficits in depressive-like behaviors, and demonstrate that bypassing low SST+ cell function via alpha5-PAM represents a targeted antidepressant strategy. ### Competing Interest Statement Funding and Disclosure C.F. and T.P. were supported by CAMH Discovery Fund fellowships. C.F. also received an Ontario Graduate Scholarship during the studies. M.B. is supported by a NARSAD young investigator award from the Brain & Behavior Research Foundation (#24034) and the CAMH Discovery Seed Fund and the Canadian Institutes of Health Research (PJT-165852). E.S. was supported by the Brain & Behavior Research Foundation (#25637) and Canadian Institutes of Health Research (PJT-153175). The project was also supported by the Campbell Family Mental Health Research Institute. D.K., G.L., P.M., J.C., E.S., M.B. and T.P. are co-inventors or listed on U.S. patent applications that cover GABAergic ligands and/or their use in brain disorders. E.S. is co-Founder of Alpha Cog, a biotech company developing ligands, including GL-II-73, as procognitive therapeutics. C.F. and K.M. have no conflicts-of-interest to disclose. Acknowledgements We acknowledge the hard work of CAMH institutional animal facility staff for their assistance in breeding, genotyping, and maintaining colonies. Special thanks to K.F., G.F., and K.D. Special thanks to Dr. Bryan Roth for providing DREADD vectors (Addgene #44362) and Drs. Gradinaru and Deverman for the AAV-PHP.eB serotype technology. Thanks also to the Penn Vector Core for packaging and production of AAV-PHP.eB serotype control viruses (Addgene #50459).

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