Chemogenetic activation of microglial Gi signaling decreases microglial surveillance and impairs neuronal synchronization

作者：Shunyi Zhao, Lingxiao Wang, Dimitrios Kleidonas, Fangfang Qi, Yue Liang, Jiaying Zheng, Anthony D. Umpierre, Long‐Jun Wu · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ado7829 · 被引用次数：10 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Neuroscience and Neuropharmacology Research、Neurogenesis and neuroplasticity mechanisms

Microglia actively survey the brain and dynamically interact with neurons to maintain brain homeostasis. Microglial Gi protein-coupled receptors (Gi-GPCRs) play a critical role in microglia-neuron communications. However, the impact of temporally activating microglial Gi signaling on microglial dynamics and neuronal activity in the homeostatic brain remains largely unknown. In this study, we used Gi-based designer receptors exclusively activated by designer drugs (Gi-DREADD) to selectively and temporally modulate microglial Gi signaling pathway. By integrating this chemogenetic approach with in vivo two-photon imaging, we observed that exogenous activation of microglial Gi signaling transiently inhibited microglial process dynamics, reduced neuronal activity, and impaired neuronal synchronization. These altered neuronal functions were associated with a decrease in interactions between microglia and neuron somata. Together, this study demonstrates that acute, exogenous activation of microglial Gi signaling regulates neuronal circuit function, offering a potential pharmacological target for the neuromodulation through microglia.