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Electroconvulsive Seizures in Rats and Fractionation of Their Hippocampi to Examine Seizure-induced Changes in Postsynaptic Density Proteins
Published on: August 15, 2017
Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of
Neta Rimmerman1, Hodaya Verdiger1, Hagar Goldenberg1
1Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
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.
Insights
Microglia are crucial for electroconvulsive stimulation
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Major depression involves microglia, but their role in antidepressant treatments is unclear.
- Microglia-dependent pathways' contribution to antidepressant procedures requires investigation.
Purpose of the Study:
- Investigate microglia's role in depression reversal by electroconvulsive stimulation (ECS).
- Examine the impact of microglia depletion on ECS efficacy.
- Identify molecular targets for novel antidepressant therapies.
Main Methods:
- Utilized a chronic unpredictable stress (CUS) mouse model of depression.
- Administered microglia-depleting agent PLX5622 and minocycline.
- Performed hippocampal RNA-Seq and immunohistochemical analyses.
- Tested lymphocyte-activating gene-3 (LAG3) monoclonal antibody treatment.
Main Results:
- Microglia depletion abrogated ECS's antidepressant and pro-neurogenesis effects.
- ECS altered neurogenesis, dopamine signaling, and immune checkpoint genes, including microglial LAG3.
- LAG3 antibody administration rescued depressive-like symptoms and neurogenesis impairment.
Conclusions:
- Brain microglial LAG3 is essential for ECS antidepressant effects.
- Microglial LAG3 represents a potential therapeutic target for depression.
