Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation

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 α5-GABA-A receptor positive allosteric modulators (α5-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 α5-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 α5-PAM represents a targeted antidepressant strategy. Significance Statement Human and animal studies demonstrate somatostatin-positive GABAergic interneuron (“SST+ cell”) deficits as contributing factors to the pathology of major depressive disorder (MDD). These changes involve reduced SST and GABAergic markers, occurring across corticolimbic brain regions. Studies have identified roles for SST+ cells in regulating mood and cognitive functions, but employed genetic or region-specific ablation that is not representative of disease-related processes. Here, we developed a chemogenetic mouse model of brain-wide low SST+ cell function. This model confirmed a role for SST+ cells in regulating anxiety- and anhedonia-like behaviors, overall behavioral emotionality, and impaired working memory. We next showed that a positive allosteric modulator at α5-GABA-A receptors (α5-PAM, GL-II-73) rescued behavioral deficits induced by low SST+ cell function. These findings support a central role for brain-wide low SST+ cell function in MDD and validate targeting α5-GABA-A receptors as a therapeutic modality across MDD symptom dimensions.