2. Academic Validation
  3. Microglia modulate general anesthesia through P2Y12 receptor

Microglia modulate general anesthesia through P2Y12 receptor

  • Curr Biol. 2023 May 6;S0960-9822(23)00529-8. doi: 10.1016/j.cub.2023.04.047.
Kelei Cao 1,  Liyao Qiu 1,  Xuan Lu 2,  Weiying Wu 1,  Yaling Hu 1,  Zhicheng Cui 3,  Chao Jiang 2,  Yuxiang Luo 1,  Yujin Shao 1,  Wang Xi 4,  Ling-Hui Zeng 5,  Han Xu 1,  Huan Ma 1,  Zhi Zhang 3,  Jiyun Peng 6,  Shumin Duan 7,  Zhihua Gao 8
Affiliations

Affiliations

  • 1 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
  • 2 Spine Lab, Department of Orthopedic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 3 School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 4 Interdisciplinary Institute of Neuroscience and Technology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
  • 5 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 6 Institute of Life Science, Nanchang University, Nanchang, Jiangxi 330031, China.
  • 7 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 8 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 37167975 DOI: 10.1016/j.cub.2023.04.047
Abstract

General anesthesia (GA) is an unconscious state produced by anesthetic drugs, which act on neurons to cause overall suppression of neuronal activity in the brain. Recent studies have revealed that GA also substantially enhances the dynamics of microglia, the primary brain immune cells, with increased process motility and territory surveillance. However, whether microglia are actively involved in GA modulation remains unknown. Here, we report a previously unrecognized role for microglia engaging in multiple GA processes. We found that microglial ablation reduced the sensitivity of mice to anesthetics and substantially shortened duration of loss of righting reflex (LORR) or unconsciousness induced by multiple anesthetics, thereby promoting earlier emergence from GA. Microglial repopulation restored the regular anesthetic recovery, and chemogenetic activation of microglia prolonged the duration of LORR. In addition, anesthesia-accompanying analgesia and hypothermia were also attenuated after microglial depletion. Single-cell RNA sequencing analyses showed that anesthesia prominently affected the transcriptional levels of chemotaxis and migration-related genes in microglia. By pharmacologically targeting different microglial motility pathways, we found that blocking P2Y12 receptor (P2Y12R) reduced the duration of LORR of mice. Moreover, genetic ablation of P2Y12R in microglia also promoted quicker recovery in mice from anesthesia, verifying the importance of microglial P2Y12R in anesthetic regulation. Our work presents the first evidence that microglia actively participate in multiple processes of GA through P2Y12R-mediated signaling and expands the non-immune roles of microglia in the brain.

Keywords

P2Y(12)R; analgesia; general anesthesia; microglia.

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