Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

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.

Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.

BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression. METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS. RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice. LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored. CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.

Bullatine A has an antidepressant effect in chronic social defeat stress mice; Implication of microglial inflammasome.

Inflammatory microglia and P2X7R are involved in the development of stress-induced depression. Endoplasmic reticulum (ER) stress and mitochondrial damage play an important role in depression and microglial activation. Bullatine A (BLA) has anti-inflammatory and anti-rheumatic effects, and can be used as a P2X7R antagonist. We found that Bullatine A can effectively inhibit the calcium overload of mitochondria and the increase of ER and mitochondrial colocalization caused by eATP (extracellular ATP) in BV2-cells. Bullatine A can also inhibit the activation of PERK-elF-2α unfolded protein response (UPR), lysosome production and the increase of NLRP3 inflammasome protein expression in BV2-cells Both intragastric administration and intra-hippocampal microinjection of Bullatine A can significantly improve the despair behavior but not anhedonia of Chronic chronic social defeat stress (CSDS) mice. Bullatine A may have a beneficial therapeutic effect in treating diseases related to stress stimulation, such as depression.