Client Publication | Advanced Science | Discovery of Glial Cell Interaction Mechanism in Depression by the Teams of Jin Yu and Yuqiu Zhang

Release time：2025-09-19 14:52:07

Numerous studies have shown that microglial activation and astrocytic atrophy/loss are key pathological features of depression. During stress, large amounts of extracellular ATP (eATP) are released, which—recognized as damage-associated molecular patterns (DAMPs)—can specifically trigger microglial activation via the P2X7 receptor (P2X7R). However, the specific activation state of microglia under elevated eATP conditions, and how this leads to astrocytic atrophy and loss, remain unclear.

A collaborative study by Professor Jin Yu from the School of Basic Medical Sciences and Professor Yuqiu Zhang from the Institute of Brain Science at Fudan University reveals that chronic stress induces microglial activation in the hippocampus, leading to the release of interleukin-6 (IL-6), which in turn causes astrocytic atrophy and loss. These mechanisms are associated with stress-induced depression-like behaviors. On March 20, 2025, this research was published online as a Research Article in Advanced Science, titled “Microglia-Derived Interleukin-6 Triggers Astrocyte Apoptosis in the Hippocampus and Mediates Depression-Like Behavior.”

https://doi.org/10.1002/advs.202412556

In this study, the researchers employed a chronic social defeat stress (CSDS) model to induce anxiety- and depression-like behaviors in mice. Through 3D reconstruction, magnetic bead-based astrocyte isolation, transcriptomic sequencing, and transmission electron microscopy, they observed that CSDS not only induced behavioral phenotypes of anxiety and depression but also led to astrocyte atrophy and apoptosis in the hippocampus.

Microglial activation was also identified as a key pathological feature induced by the CSDS model. Notably, microglial activation in the hippocampus occurred earlier than astrocytic changes following each episode of social defeat stress, suggesting that activated microglia might play a crucial role in driving astrocyte apoptosis. Further investigation revealed significantly elevated IL-6 expression in activated microglia in the CSDS model compared to controls. In vitro experiments subsequently confirmed that IL-6 released by activated microglia could induce astrocyte apoptosis.

Based on these findings, the researchers demonstrated that either genetic deletion of the P2X7R or pharmacological inhibition of microglial activation using minocycline markedly alleviated CSDS-induced microglial activation, IL-6 release, astrocyte apoptosis, and depression-like behaviors. These results highlight the critical role of P2X7R-mediated microglial activation and IL-6 release in promoting astrocyte apoptosis and depressive phenotypes under chronic stress.

Finally, selective knockdown of IL-6 in microglia or IL-6 receptor (IL-6R) in astrocytes using genetic approaches also effectively mitigated CSDS-induced anxiety- and depression-like behaviors and astrocytic atrophy. These results suggest that the IL-6/IL-6R signaling pathway is a key driver of astrocyte apoptosis and depressive phenotypes in the CSDS model.

In summary, this study reveals that chronic stress-induced upregulation of IL-6 in microglia leads to astrocyte apoptosis, thereby promoting the development of depression-like behaviors in mice. These findings offer potential therapeutic targets for the clinical treatment of depression.

Schematic: Illustration of IL-6 released by microglia in the hippocampus inducing astrocyte apoptosis and mediating anxiety- and depression-like behaviors.

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Client Publication | Advanced Science | Discovery of Glial Cell Interaction Mechanism in Depression by the Teams of Jin Yu and Yuqiu Zhang

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Client Publication | Advanced Science | Discovery of Glial Cell Interaction Mechanism in Depression by the Teams of Jin Yu and Yuqiu Zhang

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