Zhao Youyi, Zhao Ya, Liang Lirong, Chen Andi, Li Yuqian, Liu Ke, Xie Rougang, Mao Honghui, Ren Boyang, Huang Bosong, Shi Changhong, Shao Zhicheng, Wu Shengxi, Wang Yazhou, Zhang Hui
State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research, Center for Dental Materials and Advanced Manufacture, Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, P. R. China.
Department of Neurobiology and Institute of Neurosciences, School of Basic Medicine, Fourth Military Medical University, Xi'an, P. R. China.
Exp Mol Med. 2025 Apr;57(4):745-758. doi: 10.1038/s12276-025-01425-0. Epub 2025 Apr 1.
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/Ca signaling and multiple cell migration-related genes. Overexpressing DVL-1 enhanced the Ca 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/Ca 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.
早期接触全身麻醉剂是否会损害人类大脑发育仍在讨论中。动物研究已证明，新生儿期反复/长时间接触七氟醚（Sev，一种常用的儿科麻醉剂）具有多种神经毒性。其对人类神经发育的影响仍不明确。在此，通过研究源自两个人类胚胎干细胞系的神经祖细胞、人类大脑类器官和人类神经元嵌合小鼠，我们发现，虽然七氟醚在体外会抑制人类神经祖细胞的神经元分化和突触形成，但它仅在体内抑制人类神经元迁移。对人类神经元进行化学遗传学激活可挽救七氟醚预处理的人类神经元嵌合小鼠的细胞迁移缺陷和社交功能障碍。从机制上讲，七氟醚会抑制DVL-1/Ca信号传导以及多个与细胞迁移相关的基因。过表达DVL-1可增强七氟醚预处理的嵌合小鼠的Ca反应、神经元迁移和社交功能。此外，通过高频经颅磁刺激对人类神经元进行特异性调节，不仅可以激活DVL-1/Ca信号传导，还可以改善嵌合小鼠中的人类神经元迁移和社交功能。我们的数据表明，早期接触七氟醚通过抑制DVL-1信号传导对人类神经元迁移具有毒性，并且经颅磁刺激可能具有潜在的治疗作用。
