Microglia‐Derived Interleukin‐6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression‐Like Behavior

Abstract In patients with major depressive disorder (MDD) and animal models of depression, key pathological hallmarks include activation of microglia as well as atrophy and loss of astrocytes. Under certain pathological conditions, microglia can inflict damage to neurons and astrocytes. However, the precise mechanisms underlying how activated microglia induced astrocyte atrophy and loss remain enigmatic. In this study, a depression model induced by chronic social defeat stress (CSDS) is utilized. The results show that CSDS induces significant anxiety‐ and depression‐like behaviors, along with notable astrocyte atrophy and apoptosis, microglial activation, and elevated levels of microglial interleukin‐6 (IL‐6). Subsequent studies demonstrate that IL‐6 released from activated microglia promotes astrocyte apoptosis. Furthermore, the knockdown of the P2X7 receptor P2X7 receptor (P2X7R) in microglia, which is implicated in the stress response, reduces stress‐induced microglial activation, IL‐6 release, and astrocyte apoptosis. Direct inhibition of microglia by minocycline corroborates these effects. The selective knockdown of IL‐6 in microglia and IL‐6 receptors in astrocytes effectively mitigates depression‐like behaviors and reduces astrocyte atrophy. This study identifies microglial IL‐6 as a key factor that contributes to astrocyte apoptosis and depressive symptoms. Consequently, the IL‐6/IL‐6R pathway has emerged as a promising target for the treatment of depression.