In summary, our results provide helpful insights into the role of these cellular stress responses in depression-like behavior (Graphical abstract, Fig. 5d), and suggest that the formation of the IP3R3-GRP75-VDAC1 complex and the changes in the structure and function of MAMs may be significant cellular responses in microglia triggered by eATP-P2X7Rs signaling, potentially contributing to CSDS-induced microglia responses and the development of depression-like phenotypes. Here, HSPA9 is linked to depressive disorder.