Rimmerman Neta, Verdiger Hodaya, Goldenberg Hagar, Naggan Lior, Robinson Elad, Kozela Ewa, Gelb Sivan, Reshef Ronen, Ryan Karen M, Ayoun Lily, Refaeli Ron, Ashkenazi Einat, Schottlender Nofar, Ben Hemo-Cohen Laura, Pienica Claudia, Aharonian Maayan, Dinur Eyal, Lazar Koby, McLoughlin Declan M, Zvi Ayal Ben, Yirmiya Raz
Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Mol Psychiatry. 2022 Feb;27(2):1120-1135. doi: 10.1038/s41380-021-01338-0. Epub 2021 Oct 14.
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和病理生理学有关，但关于小胶质细胞依赖性分子途径在抗抑郁过程中的作用的信息却很少。在本研究中，我们通过研究集落刺激因子-1拮抗剂PLX5622对小胶质细胞的清除作用，探讨了小胶质细胞在抑郁症小鼠模型（慢性不可预测应激-CUS）及其通过电惊厥刺激（ECS）逆转中的作用。小胶质细胞清除并未改变基础行为指标或对CUS的反应性，但它完全消除了ECS对抑郁样行为和神经发生损伤的治疗作用。与ECS同时使用小胶质细胞抑制剂米诺环素也会减弱ECS的抗抑郁和促神经发生作用。海马RNA测序分析显示，ECS显著增加了与神经发生和多巴胺信号相关基因的表达，同时降低了几种免疫检查点基因的表达，特别是淋巴细胞激活基因-3（Lag3），这是唯一因ECS而显著改变的小胶质细胞转录本。这些分子变化在小胶质细胞耗竭的小鼠中均未发生。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受体表达的升高。一致地，急性或慢性全身给予LAG3单克隆抗体，该抗体很容易穿透脑实质并被发现可作为BV2小胶质细胞培养物中的直接检查点阻断剂，可迅速挽救CUS诱导的小胶质细胞改变、抑郁样症状和神经发生损伤。这些发现表明，脑小胶质细胞LAG3是新型抗抑郁治疗的一个有前景的靶点。
