Human neuron chimeric mice reveal impairment of DVL-1-mediated neuronal migration by sevoflurane and potential treatment by rTMS.

Summary

Using human cerebral organoids and human neuron chimeric mice, sevoflurane was shown to specifically impair human neuronal migration in vivo while also inhibiting differentiation and synaptogenesis in vitro. Chemogenetic activation rescued migration defects and social dysfunction, and the mechanism involves inhibition of DVL-1–mediated signaling, with potential neuromodulatory (e.g., rTMS) therapeutic implications.

Key Findings

• Sevoflurane inhibited human neuronal migration in vivo in human neuron chimeric mice, while in vitro it suppressed differentiation and synaptogenesis.
• Chemogenetic activation of human neurons rescued migration defects and social dysfunction in sevoflurane-pretreated chimeric mice.
• Mechanistic data implicate inhibition of DVL-1–mediated signaling; title suggests rTMS as a potential therapeutic approach.

Clinical Implications

Although preclinical, the findings support minimizing prolonged/repeated sevoflurane exposure in early development and motivate monitoring developmental outcomes. They also open avenues for neuromodulatory adjuncts to mitigate potential effects.

Limitations

• Preclinical models; dose/exposure paradigms may not fully reflect clinical anesthetic practices.
• Long-term functional outcomes and translatability to human infants remain uncertain.

Future Directions

Define clinically relevant exposure thresholds, validate neuromodulatory rescue (e.g., rTMS) in additional models, and integrate longitudinal neurodevelopmental assessments in at-risk clinical cohorts.