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Updated: Jun 23, 2025
Author Spotlight: Exploring Glial Influence in Experience-Dependent Synaptic Pruning During Critical Periods
Published on: March 1, 2024
Microglial EPOR Contribute to Sevoflurane-induced Developmental Fine Motor Deficits Through Synaptic Pruning in Mice
Danyi He1, Xiaotong Shi1, Lirong Liang1
1State 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.
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.
Insights
Multiple anesthesia may impair children's fine motor skills. This study reveals erythropoietin receptor (EPOR) downregulation in mice, with the peptide ARA290 reversing these effects by targeting the EPO/EPOR pathway.
Area of Science:
- Neuroscience
- Anesthesiology
- Developmental Biology
Background:
- Clinical studies suggest multiple anesthesia may increase fine motor control difficulties in children.
- The precise biological mechanisms underlying this neurodevelopmental risk remain unclear.
Purpose of the Study:
- To investigate the role of microglial erythropoietin receptor (EPOR) in sevoflurane-induced fine motor deficits in young mice.
- To explore the therapeutic potential of the EPO/EPOR signaling pathway and ARA290 peptide.
Main Methods:
- Examined EPOR expression in the medial prefrontal cortex of mice exposed to multiple sevoflurane anesthesia.
- Assessed microglial polarization, synaptic pruning, and fine motor skills following anesthesia exposure.
- Investigated the effects of intraperitoneal injection of EPO-derived peptide ARA290.
Main Results:
- Multiple sevoflurane anesthesia significantly downregulated microglial EPOR in young mice.
- Inhibition of the EPO/EPOR axis resulted in microglial polarization, excessive excitatory synaptic pruning, and impaired fine motor control.
- ARA290 administration fully reversed these anesthesia-induced neurodevelopmental and behavioral deficits.
Conclusions:
- Microglial EPOR is a critical mediator of synaptic development, influencing sevoflurane-induced fine motor dysfunction.
- Targeting the EPO/EPOR signaling pathway with ARA290 offers a potential therapeutic strategy against general anesthesia-induced neurotoxicity.
