RESUMO
BACKGROUND: Both functional brain imaging studies and autopsy reports have indicated the presence of synaptic loss in the brains of depressed patients. The activated microglia may dysfunctionally engulf neuronal synapses, leading to synaptic loss and behavioral impairments in depression. However, the mechanisms of microglial-synaptic interaction under depressive conditions remain unclear. METHODS: We utilized lipopolysaccharide (LPS) to induce a mouse model of depression, examining the effects of LPS on behaviors, synapses, microglia, microglial phagocytosis of synapses, and the C1q/C3-CR3 complement signaling pathway. Additionally, a C1q neutralizing antibody was employed to inhibit the C1q/C3-CR3 signaling pathway and assess its impact on microglial phagocytosis of synapses and behaviors in the mice. RESULTS: LPS administration resulted in depressive and anxiety-like behaviors, synaptic loss, and abnormal microglial phagocytosis of synapses in the hippocampal dentate gyrus (DG) of mice. We found that the C1q/C3-CR3 signaling pathway plays a crucial role in this abnormal microglial activity. Treatment with the C1q neutralizing antibody moderated the C1q/C3-CR3 pathway, leading to a decrease in abnormal microglial phagocytosis, reduced synaptic loss, and improved behavioral impairments in the mice. CONCLUSIONS: The study suggests that the C1q/C3-CR3 complement signaling pathway, which mediates abnormal microglial phagocytosis of synapses, presents a novel potential therapeutic target for depression treatment.
Assuntos
Complemento C1q , Complemento C3 , Depressão , Modelos Animais de Doenças , Microglia , Fagocitose , Transdução de Sinais , Sinapses , Animais , Complemento C1q/metabolismo , Microglia/metabolismo , Sinapses/metabolismo , Camundongos , Transdução de Sinais/fisiologia , Depressão/metabolismo , Fagocitose/fisiologia , Complemento C3/metabolismo , Masculino , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: The endocannabinoid system plays a crucial role in regulating mood, but the specific involvement of cannabinoid receptor type 2 (CB2R) in depression remains poorly understood. Similarly, the mechanisms by which electroacupuncture (EA) provides therapeutic benefits for depression are not clearly defined. This research aims to explore the function of CB2R in depression and examine if the therapeutic effects of EA are associated with the hippocampal CB2R system. METHODS: Mice experiencing social defeat stress (SDS) were used to model depression and anxiety behaviors. We quantified hippocampal CB2R and N-arachidonoylethanolamide (AEA) levels. The efficacy of a CB2R agonist, JWH133, in mitigating SDS-induced behaviors was evaluated. Additionally, EA's impact on CB2R and AEA was assessed, along with the influence of CB2R antagonist AM630 on EA's antidepressant effects. RESULTS: SDS led to depressive and anxiety-like behaviors, with corresponding decreases in hippocampal CB2R and AEA. Treatment with JWH133 ameliorated these behaviors. EA treatment resulted in increased CB2R and AEA levels, while AM630 blocked these antidepressant effects. LIMITATIONS: The study mainly focused on the SDS model, which may not entirely reflect other depression models. Besides, further investigation is needed to understand the precise mechanisms by which CB2R and AEA contribute to EA's effects. CONCLUSIONS: The study suggests hippocampal downregulation of CB2R and AEA contributes to depression. Upregulation of CB2R and AEA in response to EA suggests their involvement in EA's antidepressant effects. These findings provide insights into the role of the hippocampal CB2R system in depression and the potential mechanisms underlying EA's therapeutic effects.
Assuntos
Canabinoides , Depressão , Camundongos , Animais , Receptores de Canabinoides , Depressão/tratamento farmacológico , Derrota Social , Canabinoides/farmacologia , Canabinoides/uso terapêutico , AntidepressivosRESUMO
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.