Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice

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.