癫痫发生
神经科学
基因剔除小鼠
小胶质细胞
钙信号传导
兰尼定受体
兴奋毒性
溶酶体
钙
海马体
信号转导
化学
细胞生物学
受体
生物
免疫学
NMDA受体
炎症
生物化学
细胞内
有机化学
酶
作者
Anthony D. Umpierre,Bohan Li,Katayoun Ayasoufi,Whitney L. Simon,Shunyi Zhao,Manling Xie,Grace Thyen,Benjamin Hur,Jiaying Zheng,Yue Liang,Dale B. Bosco,Mary Jo Maynes,Zhaofa Wu,Xinzhu Yu,Jaeyun Sung,Aaron J. Johnson,Yulong Li,Long‐Jun Wu
出处
期刊:Neuron
[Elsevier]
日期:2024-06-01
卷期号:112 (12): 1959-1977.e10
被引量:5
标识
DOI:10.1016/j.neuron.2024.03.017
摘要
Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.
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