Department of Anesthesiology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Institute of Anesthesiology, Soochow University, Suzhou, Jiangsu, China.
J Neurochem. 2024 Jun;168(6):1080-1096. doi: 10.1111/jnc.16068. Epub 2024 Feb 5.
Sevoflurane, the predominant pediatric anesthetic, has been linked to neurotoxicity in young mice, although the underlying mechanisms remain unclear. This study focuses on investigating the impact of neonatal sevoflurane exposure on cell-type-specific alterations in the prefrontal cortex (PFC) of young mice. Neonatal mice were subjected to either control treatment (60% oxygen balanced with nitrogen) or sevoflurane anesthesia (3% sevoflurane in 60% oxygen balanced with nitrogen) for 2 hours on postnatal days (PNDs) 6, 8, and 10. Behavioral tests and single-nucleus RNA sequencing (snRNA-seq) of the PFC were conducted from PNDs 31 to 37. Mechanistic exploration included clustering analysis, identification of differentially expressed genes (DEGs), enrichment analyses, single-cell trajectory analysis, and genome-wide association studies (GWAS). Sevoflurane anesthesia resulted in sociability and cognition impairments in mice. Novel specific marker genes identified 8 distinct cell types in the PFC. Most DEGs between the control and sevoflurane groups were unique to specific cell types. Re-defining 15 glutamatergic neuron subclusters based on layer identity revealed their altered expression profiles. Notably, sevoflurane disrupted the trajectory from oligodendrocyte precursor cells (OPCs) to oligodendrocytes (OLs). Validation of disease-relevant candidate genes across the main cell types demonstrated their association with social dysfunction and working memory impairment. Behavioral results and snRNA-seq collectively elucidated the cellular atlas in the PFC of young male mice, providing a foundation for further mechanistic studies on developmental neurotoxicity induced by anesthesia.
七氟醚是主要的儿科麻醉剂，已被证实会导致幼鼠的神经毒性，但其潜在机制尚不清楚。本研究重点关注新生儿七氟醚暴露对幼鼠前额叶皮质（PFC）中特定细胞类型改变的影响。新生小鼠在出生后第 6、8 和 10 天（PND）接受对照处理（60%氧气与氮气平衡）或七氟醚麻醉（3%七氟醚与 60%氧气与氮气平衡）2 小时。从 PND 31 到 37 进行行为测试和 PFC 的单细胞 RNA 测序（snRNA-seq）。机制探索包括聚类分析、差异表达基因（DEGs）的鉴定、富集分析、单细胞轨迹分析和全基因组关联研究（GWAS）。七氟醚麻醉导致小鼠社交和认知障碍。新确定的 8 个独特的特定标记基因可识别 PFC 中的 8 种不同细胞类型。对照和七氟醚组之间的大多数 DEGs 是特定细胞类型特有的。基于层身份重新定义 15 个谷氨酸能神经元亚群，揭示了它们的表达谱改变。值得注意的是，七氟醚破坏了少突胶质前体细胞（OPC）向少突胶质细胞（OL）的轨迹。在主要细胞类型中验证与疾病相关的候选基因，证明它们与社交功能障碍和工作记忆损伤有关。行为结果和 snRNA-seq 共同阐明了幼鼠雄性 PFC 的细胞图谱，为麻醉诱导发育性神经毒性的进一步机制研究提供了基础。
