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

Overview

Journal Neurosci Bull

Specialty Neurology

Date 2024 Jun 21

PMID 38907076

Authors

Danyi He

Xiaotong Shi

Lirong Liang

Youyi Zhao

Sanxing Ma

Shuhui Cao

Bing Liu

Zhenzhen Gao

Xiao Zhang

Ze Fan

Fang Kuang

Hui Zhang

Affiliations

Soon will be listed here.

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.

References

Shah Y, Xie L . Hypoxia-inducible factors link iron homeostasis and erythropoiesis. Gastroenterology. 2014; 146(3):630-42. PMC: 3943938. DOI: 10.1053/j.gastro.2013.12.031. View

Wei S, Luo C, Yu S, Gao J, Liu C, Wei Z . Erythropoietin ameliorates early brain injury after subarachnoid haemorrhage by modulating microglia polarization via the EPOR/JAK2-STAT3 pathway. Exp Cell Res. 2017; 361(2):342-352. DOI: 10.1016/j.yexcr.2017.11.002. View

Useinovic N, Near M, Cabrera O, Boscolo A, Milosevic A, Harvey R . Neonatal sevoflurane exposure induces long-term changes in dendritic morphology in juvenile rats and mice. Exp Biol Med (Maywood). 2023; 248(7):641-655. PMC: 10350807. DOI: 10.1177/15353702231170003. View

Gao C, Qian Y, Huang J, Wang D, Su W, Wang P . A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice. Mol Neurobiol. 2016; 54(10):8348-8360. DOI: 10.1007/s12035-016-0318-0. View

Robertson C, Garcia R, Gaddam S, Grill R, Hand C, Tian T . Treatment of mild traumatic brain injury with an erythropoietin-mimetic peptide. J Neurotrauma. 2012; 30(9):765-74. PMC: 3653382. DOI: 10.1089/neu.2012.2431. View

Timotius I, Roelofs R, Richmond-Hacham B, Noldus L, von Horsten S, Bikovski L . CatWalk XT gait parameters: a review of reported parameters in pre-clinical studies of multiple central nervous system and peripheral nervous system disease models. Front Behav Neurosci. 2023; 17:1147784. PMC: 10284348. DOI: 10.3389/fnbeh.2023.1147784. View

Tamura T, Aoyama M, Ukai S, Kakita H, Sobue K, Asai K . Neuroprotective erythropoietin attenuates microglial activation, including morphological changes, phagocytosis, and cytokine production. Brain Res. 2017; 1662:65-74. DOI: 10.1016/j.brainres.2017.02.023. View

Wang J, Chen H, Li H, Wang H, Zou R, Lu X . Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice. Brain Behav Immun. 2022; 109:23-36. DOI: 10.1016/j.bbi.2022.12.019. View

Zheng H, Dong Y, Xu Z, Crosby G, Culley D, Zhang Y . Sevoflurane anesthesia in pregnant mice induces neurotoxicity in fetal and offspring mice. Anesthesiology. 2013; 118(3):516-26. PMC: 3580035. DOI: 10.1097/ALN.0b013e3182834d5d. View

10.

Swartjes M, van Velzen M, Niesters M, Aarts L, Brines M, Dunne A . ARA 290, a peptide derived from the tertiary structure of erythropoietin, produces long-term relief of neuropathic pain coupled with suppression of the spinal microglia response. Mol Pain. 2014; 10:13. PMC: 3928087. DOI: 10.1186/1744-8069-10-13. View

11.

Soteros B, Sia G . Complement and microglia dependent synapse elimination in brain development. WIREs Mech Dis. 2021; 14(3):e1545. PMC: 9066608. DOI: 10.1002/wsbm.1545. View

12.

Schafer D, Lehrman E, Kautzman A, Koyama R, Mardinly A, Yamasaki R . Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012; 74(4):691-705. PMC: 3528177. DOI: 10.1016/j.neuron.2012.03.026. View

13.

Liang L, Zeng T, Zhao Y, Lu R, Guo B, Xie R . Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation. J Pineal Res. 2021; 71(4):e12771. PMC: 9285571. DOI: 10.1111/jpi.12771. View

14.

Watanabe M, Lundgren T, Saito Y, Cerami A, Brines M, Ostenson C . A Nonhematopoietic Erythropoietin Analogue, ARA 290, Inhibits Macrophage Activation and Prevents Damage to Transplanted Islets. Transplantation. 2015; 100(3):554-62. DOI: 10.1097/TP.0000000000001026. View

15.

McCann M, de Graaff J, Dorris L, Disma N, Withington D, Bell G . Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019; 393(10172):664-677. PMC: 6500739. DOI: 10.1016/S0140-6736(18)32485-1. View

16.

Knaus L, Basilico B, Malzl D, Gerykova Bujalkova M, Smogavec M, Schwarz L . Large neutral amino acid levels tune perinatal neuronal excitability and survival. Cell. 2023; 186(9):1950-1967.e25. DOI: 10.1016/j.cell.2023.02.037. View

17.

Brines M, Patel N, Villa P, Brines C, Mennini T, De Paola M . Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008; 105(31):10925-30. PMC: 2504825. DOI: 10.1073/pnas.0805594105. View

18.

Clausen N, Veno S, Astvad M, Henneberg S, Christensen K, Hansen T . [Potential neurotoxicity of general anaesthetics to the developing brain]. Ugeskr Laeger. 2014; 176(34). View

19.

Tanaka T, Kai S, Koyama T, Daijo H, Adachi T, Fukuda K . General anesthetics inhibit erythropoietin induction under hypoxic conditions in the mouse brain. PLoS One. 2012; 6(12):e29378. PMC: 3246473. DOI: 10.1371/journal.pone.0029378. View

20.

Paolicelli R, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P . Synaptic pruning by microglia is necessary for normal brain development. Science. 2011; 333(6048):1456-8. DOI: 10.1126/science.1202529. View