Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress—CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.

尽管有证据表明小胶质细胞与重度抑郁症的病因学和病理生理学有关，但关于小胶质细胞依赖性分子通路对抗抑郁程序的贡献的信息很少。在这项研究中，我们通过检查集落刺激因子 1 拮抗剂 PLX5622 对小胶质细胞耗竭的影响，研究了小胶质细胞在抑郁症小鼠模型（慢性不可预测的应激 - CUS）中的作用及其通过电休克刺激 (ECS) 的逆转。小胶质细胞耗竭并未改变基础行为指标或对 CUS 的反应，但它完全消除了 ECS 对抑郁样行为和神经发生障碍的治疗作用。小胶质细胞抑制剂米诺环素与 ECS 同时治疗也降低了 ECS 的抗抑郁和促神经发生作用。Lag3)，这是唯一被 ECS 显着改变的小胶质细胞转录本。这些分子变化都没有发生在小胶质细胞耗尽的小鼠身上。免疫组织化学分析表明，ECS 逆转了 CUS 诱导的小胶质细胞形态变化和小胶质细胞 LAG3 受体表达升高。一致地，LAG3 单克隆抗体的急性或慢性全身给药，很容易渗透到脑实质中，并被发现在 BV2 小胶质细胞培养物中作为直接检查点阻断剂，迅速挽救了 CUS 诱导的小胶质细胞改变，抑郁样症状，和神经发生障碍。这些发现表明，大脑小胶质细胞 LAG3 代表了新型抗抑郁疗法的一个有希望的目标。