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Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits

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Abstract

Clinical surgical practices have found that children who undergo multiple anesthesia may have an increased risk of deficiencies in cognition and fine motor control. Here, we report that YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified mRNA, was significantly downregulated in the prefrontal cortex of young mice after multiple sevoflurane anesthesia exposures. Importantly, sevoflurane led to a decrease in protein synthesis in mouse cortical neurons that was fully rescued by YTHDF1, suggesting that anesthesia may affect early brain development by affecting m6A-dependent mRNA translation. Transcriptome-wide experiments showed that numerous mRNA targets related to synaptic functions in the prefrontal mouse cortex were associated with m6A methylation and YTHDF1. In particular, we found that synaptophysin, a critical presynaptic protein, was specifically modified by m6A methylation and associated with YTHDF1, and m6A methylation of synaptophysin decreased with multiple sevoflurane exposures. Importantly, we showed that fine motor control skills and cognitive functions were impaired in mice with multiple anesthesia exposures, and these effects were fully reversed by reintroducing YTHDF1 through a blood-brain barrier (BBB)-crossing viral delivery system. Finally, we found that the fine motor skills in children who underwent prolonged anesthesia were compromised 6 months after surgery. Our findings indicated that impairment in the translational regulation of mRNA via N6-methyladenosine methylation is a potential mechanism underlying the effects of anesthesia on neural development in the young brain.

Graphical abstract

1. N6-methyladenosine (m6A) modifications were involved in anesthesia-induced neurotoxicity.

2. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor deficits in young mice.

3. YTHDF1, a m6A reader protein, rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.

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Availability of data and material

The datasets generated during and/or analyses during the current study are available in public database. Details were shown in “Materials and Methods 17. Data deposition.”

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Funding

This work was supported by the National Nature Science Foundation of China (NSFC) Grants (#82071177, #81771132, #81970990, #81571028, #31625013, #81941015), Shanghai Brain-Intelligence Project from STCSM (#16JC1420501), the Strategic Priority Research Program of the Chinese Academy of Sciences (#XDBS01060200), and the Shanghai Municipal Science and Technology Major Project (#2018SHZDZX05). The research is supported by the Open Large Infrastructure Research of Chinese Academy of Sciences. National Key R&D Program of China (#2017YFA0105201) and the CAMS Innovation Fund for Medical Sciences (#CIFMS 2016-I2M-2-001). Foundation of Shanghai Municipal Health Commission (#21840052); Shanghai Jiao Tong University School of Medicine Two-hundred Talent-20191818; Cross disciplinary Research Fund of Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine JYJC202002; Wu Jieping Medical Foundation 320.6750.19089-74.

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Contributions

Conceptualization, H.J, L.Z, Z.L.Q, and T.Z.; methodology, L.Z, Y.Y.C, Z.H.X, J.J.L, J.Y, J.W. C.W, W.D.C; investigation, H.J, L.Z, and Z.L.Q.; writing – original draft, L.Z, Y.Y.C, and N.M.W.; writing – review and editing, H.J, L.Z, Z.L.Q, and T.Z; funding acquisition, H.J, L.Z, and Z.L.Q.; supervision, H.J and Z.L.Q.

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Correspondence to Lei Zhang, Zilong Qiu or Hong Jiang.

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The use of rhesus macaque in research at the Institute of Laboratory Animal Science was approved by the Institutional Animal Care and Use Committee (protocol number #XC17001). The mice protocol was approved by the Institutional Animal Care and Use Committee at Shanghai Ninth People’s Hospital, Shanghai, China. The study protocol was approved by the Human Research Ethics Committee of Shanghai Ninth People’s Hospital and Shanghai Jiao Tong University in Shanghai, P. R. China [SH9H-2019-T293-2] (the clinical trial number is NCT04291274).

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Zhang, L., Cheng, Y., Xue, Z. et al. Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits. Cell Biol Toxicol 38, 347–369 (2022). https://doi.org/10.1007/s10565-021-09601-4

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