Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits
Lei Zhang1, Yanyong Cheng2, Zhenyu Xue2
1Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. weiymzhl@126.com.
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. 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.
Insights
Anesthesia can harm young brain development by disrupting N6-methyladenosine (m6A) mRNA translation. Restoring the YTHDF1 protein rescues cognitive and motor deficits caused by anesthesia exposure in mice.
Area of Science:
- Neuroscience
- Molecular Biology
- Developmental Biology
Background:
- Multiple anesthesia exposures in children are linked to cognitive and motor skill deficits.
- N6-methyladenosine (m6A) modifications regulate gene expression, but their role in anesthesia-induced neurodevelopmental effects is unclear.
Purpose of the Study:
- To investigate the impact of sevoflurane anesthesia on m6A-dependent mRNA translation in the developing brain.
- To identify key proteins involved in mediating anesthesia's effects on neural function and behavior.
Main Methods:
- Examined YTHDF1 protein levels in the prefrontal cortex of mice after sevoflurane exposure.
- Assessed protein synthesis in mouse cortical neurons and rescue effects of YTHDF1.
- Conducted transcriptome-wide analysis of m6A-modified mRNAs and YTHDF1 targets.
- Utilized a blood-brain barrier-crossing viral vector to reintroduce YTHDF1 in vivo.
- Evaluated fine motor skills and cognitive functions in mice and analyzed clinical data from children.
Main Results:
- Sevoflurane anesthesia significantly downregulated YTHDF1 in the mouse prefrontal cortex.
- Anesthesia reduced protein synthesis, which was fully restored by YTHDF1.
- Numerous synaptic function-related mRNAs were m6A-modified and associated with YTHDF1, including synaptophysin.
- Anesthesia-induced deficits in fine motor control and cognition in mice were reversed by YTHDF1 restoration.
- Children with prolonged anesthesia showed compromised fine motor skills post-surgery.
Conclusions:
- Anesthesia impairs early brain development by disrupting m6A-dependent mRNA translation.
- YTHDF1 plays a crucial role in mitigating anesthesia-induced neurotoxicity and functional deficits.
- Targeting m6A translation pathways offers a potential therapeutic strategy for anesthesia-related neurodevelopmental issues.
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