Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation.

Autor: Rimmerman N; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Verdiger H; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Goldenberg H; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Naggan L; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Robinson E; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Kozela E; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Gelb S; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Reshef R; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Ryan KM; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.; Department of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, James Street, Dublin, Ireland., Ayoun L; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Refaeli R; Edmond & Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel., Ashkenazi E; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Schottlender N; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Ben Hemo-Cohen L; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Pienica C; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Aharonian M; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Dinur E; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., Lazar K; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel., McLoughlin DM; Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.; Department of Psychiatry, Trinity College Dublin, St. Patrick's University Hospital, James Street, Dublin, Ireland., Zvi AB; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel., Yirmiya R; Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel. razyirmiya@huji.ac.il.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 Feb; Vol. 27 (2), pp. 1120-1135. Date of Electronic Publication: 2021 Oct 14.
DOI: 10.1038/s41380-021-01338-0
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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