Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice
Danyi He1 · Xiaotong Shi1 · Lirong Liang1 · Youyi Zhao1 · Sanxing Ma1 · Shuhui Cao1 · Bing Liu1 · Zhenzhen Gao1 · Xiao Zhang1 · Ze Fan1,2 · Fang Kuang2 · Hui Zhang11 State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi’an 710032, China
2 Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
Abstract
Clinical researches including the Mayo Anesthesia Safety in Kids (MASK) study have found that children undergoing multiple anesthesia may have a higher risk of fine motor control difficulties. However, the underlying mechanisms remain elusive. Here, we report that erythropoietin receptor (EPOR), a microglial receptor associated with phagocytic activity, was significantly downregulated in the medial prefrontal cortex of young mice after multiple sevoflurane anesthesia exposure. Importantly, we found that the inhibited erythropoietin (EPO)/EPOR signaling axis led to microglial polarization, excessive excitatory synaptic pruning, and abnormal fine motor control skills in mice with multiple anesthesia exposure, and those above-mentioned situations were fully reversed by supplementing EPO-derived peptide ARA290 by intraperitoneal injection. Together, the microglial EPOR was identified as a key mediator regulating early synaptic development in this study, which impacted sevoflurane-induced fine motor dysfunction. Moreover, ARA290 might serve as a new treatment against neurotoxicity induced by general anesthesia in clinical practice by targeting the EPO/EPOR signaling pathway.
Keywords
Erythropoietin; Microglia; Synaptic pruning; Sevofurane; Fine motor defcits
