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. Every year, millions of children and pregnant women undergo surgery with anesthesia, raising concerns about its safety. Some studies suggest that anesthesia, like sevoflurane (Sev), might harm brain development in young children, but results are mixed. Researchers explored Sev′s effects on human neurons using a new model involving human-mouse chimeric brains, which enabled them to observe the real-life effects of anesthesia. They exposed these models to Sev and found that while many toxic effects seen in lab settings were not present in living organisms, Sev did hinder human neuronal migration, leading to social behavior issues in human neuron chimeric mice. Further, they discovered that Sev affects a specific signaling pathway, which is crucial for neuron movement. By using transcranial magnetic stimulation (TMS), they could partially reverse these effects. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.