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.

中文翻译：

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生长抑素阳性GABA神经元沉默诱导的抑郁样行为可通过α5 GABA-A受体增强来挽救

简介：生长抑素阳性γ-氨基丁酸中间神经元（SST +细胞）的缺陷与重度抑郁症（MDD）相关，并且根据啮齿动物研究表明，慢性应激会导致SST +细胞功能障碍与抑郁样缺陷之间存在因果关系诱导整个皮质小脑区的SST + GABA细胞表型低，降低Sst，SST +细胞或GABA功能可诱导抑郁样行为，抑制SST +细胞功能具有抗抑郁作用。最近的研究发现，化合物优先增强介导SST +细胞功能的受体与α5-GABA-A受体阳性变构调节剂（α5-PAM）的抗抑郁作用。一起，证据表明，SST +细胞调节在MDD中被破坏的情绪和认知功能，而抢救SST +细胞功能可能代表了一种有前途的治疗策略。方法：我们开发了一种对全脑SST +细胞进行化学生成沉默的小鼠模型，并在急性或亚慢性沉默30分钟后采用行为特征来鉴定对MDD相关行为的贡献。然后，我们评估了alpha5-PAM，GL-II-73是否可以挽救SST +细胞沉默诱导的行为缺陷。结果：全脑的SST +细胞沉默诱导了与压力有关的疾病的特征，包括神经元活动和血浆皮质酮水平升高，焦虑症和类似快感的行为增加以及短期记忆受损。GL-II-73在全脑SST +细胞沉默诱导的所有行为缺陷中导致了类似抗抑郁药的改善。结论：我们的数据验证了SST +细胞是情绪和认知功能的调节剂，支持SST +细胞缺陷在抑郁样行为中的作用，并证明通过alpha5-PAM绕过低SST +细胞功能代表了靶向抗抑郁策略。