Zhong Hongyu, Xue Rou, Han Yaning, Liu Lei, Zhao Jianshuai, Cai Min, Wang Sa, Wei Pengfei, Zhao Guangchao, Dong Hailong
Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
Key Laboratory of Anesthesiology, Ministry of Education of China, Xi'an, 710032, China.
Mol Psychiatry. 2025 Mar 11. doi: 10.1038/s41380-025-02949-7.
The impact of general anesthetics on neurodevelopment is highly controversial in terms of clinical and preclinical studies. Evidence mounted in recent years indicated development of social cognitions was more susceptible to general anesthesia in early life. However, the behavioral characterization during adolescence and underlying mechanisms remains unclear. Herein, we observed that early postnatal S-ketamine exposure specifically induced deficits in sociability and social cognition via a machine learning assistant behavioral analysis toolbox- Social Behavioral Atlas (SBeA). Furthermore, S-ketamine exposure constantly activates microglia in the prefrontal cortex (PFC), mediating excessive synaptic pruning and dendritic structural abnormalities, leading to overexcitation of excitatory synaptic transmission. Notably, S-ketamine exposure activated Stat1-Arg1 pathway in microglia. Downregulating Arg1 expression or prophylactic administrating Arg1 selective inhibitor nor-NOHA could reverse microglial overactivation and attenuate the neurodevelopmental disturbance induced by S-ketamine exposure. Our study identifies the abnormal behavioral phenotypes in adolescence induced by early postnatal S-ketamine exposure and reveals a potential target for preventing anesthesia-related neurodevelopmental abnormalities.
就临床和临床前研究而言，全身麻醉对神经发育的影响极具争议性。近年来积累的证据表明，社会认知的发展在生命早期更容易受到全身麻醉的影响。然而，青春期的行为特征及潜在机制仍不清楚。在此，我们观察到出生后早期暴露于S-氯胺酮会通过机器学习辅助行为分析工具箱——社会行为图谱（SBeA）特异性地导致社交能力和社会认知缺陷。此外，S-氯胺酮暴露持续激活前额叶皮质（PFC）中的小胶质细胞，介导过度的突触修剪和树突结构异常，导致兴奋性突触传递过度兴奋。值得注意的是，S-氯胺酮暴露激活了小胶质细胞中的Stat1-Arg1通路。下调Arg1表达或预防性给予Arg1选择性抑制剂nor-NOHA可逆转小胶质细胞过度激活，并减轻S-氯胺酮暴露诱导的神经发育障碍。我们的研究确定了出生后早期S-氯胺酮暴露在青春期诱导的异常行为表型，并揭示了一个预防麻醉相关神经发育异常的潜在靶点。
