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Updated: Jun 23, 2025
Animal Models of Depression - Chronic Despair Model CDM
Published on: September 23, 2021
Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by
Jia-Rui Zhang1, Shi-Yu Shen1,2, Meng-Ying Zhai1
1Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
Abstract:
Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.
Insights
Mitochondria-associated membranes (MAMs) and a specific protein complex are key to microglial stress responses and depression-like behaviors in mice. This pathway, involving ER-mitochondria communication, offers new therapeutic targets for depression.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Extracellular ATP (eATP) and P2X7 receptor signaling are implicated in microglial NLRP3 inflammasome activation and depression.
- Microglial cellular stress responses to eATP and stress, particularly involving mitochondria-associated membranes (MAMs), are not well understood.
- MAMs regulate calcium transport and homeostasis between the endoplasmic reticulum (ER) and mitochondria, influencing cellular stress.
Purpose of the Study:
- To investigate the role of MAMs in microglial responses to chronic social defeat stress (CSDS) and depression-like behaviors.
- To explore how MAMs mediate ER-mitochondria communication and cellular stress in microglia under stress and eATP exposure.
- To elucidate the involvement of the IP3R3-GRP75-VDAC1 complex within MAMs in microglial dysfunction and depression.
Main Methods:
- Induction of depression-like behaviors in male mice using CSDS.
- Analysis of ER stress, MAMs, mitochondrial damage, and the IP3R3-GRP75-VDAC1 complex in hippocampal microglia.
- Experimental manipulation of GRP75 expression in BV2 cells and mouse models (Cx3cr1CreER/+Hspa9f/+ mice) to assess its impact on microglial function and behavior.
Main Results:
- CSDS induced ER stress, MAM modifications, mitochondrial damage, and IP3R3-GRP75-VDAC1 complex formation in microglia, correlating with depression-like behaviors.
- eATP exposure mimicked CSDS effects on microglia, including ER stress and mitochondrial dysfunction.
- GRP75 knockdown impaired ER-mitochondria contact, calcium transfer, and reduced eATP-induced ER stress, mitochondrial damage, and NLRP3 inflammasome aggregation.
- Reduced GRP75 in mice decreased depression-like behaviors, NLRP3 inflammasome aggregation, and ER-mitochondria contacts during CSDS.
Conclusions:
- MAMs, specifically the IP3R3-GRP75-VDAC1 complex, are crucial for ER-mitochondria communication in microglia.
- This MAMs-mediated pathway contributes significantly to microglial stress responses and the development of depression-like phenotypes in male mice.
- Targeting MAMs and the GRP75-containing complex presents a potential therapeutic strategy for depression.
