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

Abstract

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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Fig. 1: Effects of microglia depletion on body weight and behavior.
Fig. 2: Involvement of microglia in the antidepressant and neurogenesis-enhancing effects of ECS.
Fig. 3: ECS-induced molecular changes are abrogated in microglia-depleted mice.
Fig. 4: Effects of ECS on microglia number, morphology and LAG-expression.
Fig. 5: Effects of acute and chronic administration of LAG3 mAb on depressive-like symptomatology, microglial morphology and neurogenesis in CUS-exposed mice.
Fig. 6: A model depicting the role of microglia in the development of chronic unpredictable stress (CUS)-induced depression and its reversal by ECS.

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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Acknowledgements

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).

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NR and RY designed and directed the studies. HV, HG, LN, ER, EK RR, LA, SG, RR, EA, NS, LBH, CP, MA, ED, and KL performed the experiments. NR, HV, HG, LN, EK RR, KMR, DMM, ABZ, and RY analyzed the data. RY designed the concept and obtained funding. NR and RY wrote the manuscript.

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Correspondence to Raz Yirmiya.

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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

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