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

Abstract

Whether early exposure to general anesthetics hurts human brain development is still under discussion. Animal studies have documented multiple neurotoxicities of repeated/prolonged exposure to sevoflurane (Sev, a commonly used pediatric anesthetic) at the neonatal stage. Its effects on human neural development remain elusive. Here, by investigating neural progenitor cells derived from two human embryonic stem cell lines, human cerebral organoids and human neuronal chimeric mice, we found that, although Sev inhibits neuronal differentiation and synaptogenesis of human neural progenitor cells in vitro, it only inhibits human neuronal migration in vivo. Chemogenetic activation of human neurons rescued the defects of cell migration and social dysfunction of Sev-pretreated human neuronal chimeric mice. Mechanistically, Sev inhibits DVL-1/Ca²⁺ signaling and multiple cell migration-related genes. Overexpressing DVL-1 enhanced the Ca²⁺ response, neuronal migration and social function of Sev-pretreated chimeric mice. Furthermore, specific modulation of human neurons by high-frequency transcranial magnetic stimulation not only activated DVL-1/Ca²⁺ signaling but also improved human neuronal migration and social function in chimeric mice. Our data demonstrate that early Sev exposure is toxic to human neuronal migration via inhibiting DVL-1 signaling and that transcranial magnetic stimulation could be potentially therapeutic.