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.
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Data and materials availability
The RNA-Seq data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE123027.
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We thank Ms. Zehava Cohen for help in preparation of the figures. We thank Dr. Gilgi Friedlander from the Nancy & Stephen Grand Israel National Center for Personalized Medicine (G-INCPM) for help with RNA-Seq and analysis. Postmortem brain tissue was donated by The Stanley Medical Research Institute brain collection. This research was supported by the Israel Science Foundation grant No. 1379/16 (to RY).
D.M.M. has received speaker’s honoraria from MECTA and Otsuka and an honorarium from Janssen for participating in an esketamine advisory board meeting. The other authors declare no competing financial interests in relation to the work in this paper.
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Rimmerman, N., Verdiger, H., Goldenberg, H. et al. Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01338-0