The Notch signaling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether the Notch signaling pathway was involved in the neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal exposure to ketamine. On postnatal day 7 (PND-7), male Sprague–Dawley (SD) rats were intraperitoneally injected with 40 mg/kg ketamine four consecutive times (40 mg/kg × 4) at 1-h intervals. Notch ligand Jagged1 (0.5 mg/kg) and lentivirus overexpressing the Notch1 intracellular domain (LV-NICD1) were microinjected into the hippocampal dentate gyrus (DG) 1 h or 4 days before ketamine administration, respectively. The expression of Notch1 signaling pathway-related proteins was detected by Western blotting 24 h after ketamine administration. The proliferation and differentiation of the neural stem cells (NSCs) in the hippocampal DG were evaluated by double immunofluorescence staining 24 h after treatment. Moreover, changes in hippocampus-dependent spatial memory of 2-month-old rats were investigated with the Morris water maze test. Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, NICD1, and hairy enhancer of split 1 (Hes1); inhibited the proliferation and astrocytic differentiation of NSCs; and promoted the differentiation of neurons. Neonatal exposure to ketamine caused deficits in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. Microinjection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1-related proteins in the hippocampal DG, attenuated the ketamine-mediated decrease in NSC proliferation and differentiation, and improved the cognitive function of 2-month-old rats after neonatal exposure to ketamine. These results suggest that neonatal exposure to ketamine in rats inhibits the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood. The Notch1 signaling pathway may be involved in the impairment of hippocampus-dependent learning and memory during adulthood caused by neonatal exposure to ketamine. These findings contribute to further understanding the neurotoxicity induced by neonatal exposure to ketamine and the underlying mechanisms.

Notch信号通路在神经发生的调节中起重要作用。本研究的目的是调查 Notch 信号通路是否与新生儿接触氯胺酮引起的神经发生障碍和长期神经认知功能障碍有关。在出生后第 7 天 (PND-7)，雄性 Sprague-Dawley (SD) 大鼠以 1 小时的间隔连续四次 (40 mg/kg × 4) 腹膜内注射 40 mg/kg 氯胺酮。Notch 配体 Jagged1 (0.5 mg/kg) 和过表达 Notch1 胞内结构域 (LV-NICD1) 的慢病毒分别在氯胺酮给药前 1 小时或 4 天显微注射到海马齿状回 (DG) 中。在氯胺酮给药后24小时通过Western印迹检测Notch1信号通路相关蛋白的表达。处理后24小时通过双重免疫荧光染色评估海马DG中神经干细胞（NSCs）的增殖和分化。此外，通过莫里斯水迷宫试验研究了 2 个月大大鼠的海马依赖性空间记忆的变化。新生大鼠氯胺酮麻醉降低了 Jagged1、Notch1、NICD1 和多毛增强子 split 1 (Hes1) 的表达水平；抑制NSCs的增殖和星形胶质细胞分化；并促进神经元的分化。新生儿接触氯胺酮导致 2 个月大大鼠海马依赖的空间参考记忆任务出现缺陷。显微注射 Jagged1 或 LV-NICD1 逆转氯胺酮对海马 DG 中 Notch1 相关蛋白表达的抑制作用，减轻氯胺酮介导的 NSC 增殖和分化减少，并改善 2 个月大大鼠在新生儿暴露于氯胺酮后的认知功能。这些结果表明，新生大鼠接触氯胺酮可抑制海马神经干细胞的增殖和分化，并损害成年期的神经认知功能。Notch1 信号通路可能与新生儿暴露于氯胺酮引起的成年期海马依赖性学习和记忆障碍有关。这些发现有助于进一步了解新生儿接触氯胺酮引起的神经毒性及其潜在机制。这些结果表明，新生大鼠接触氯胺酮可抑制海马神经干细胞的增殖和分化，并损害成年期的神经认知功能。Notch1 信号通路可能与新生儿暴露于氯胺酮引起的成年期海马依赖性学习和记忆障碍有关。这些发现有助于进一步了解新生儿接触氯胺酮引起的神经毒性及其潜在机制。这些结果表明，新生大鼠接触氯胺酮可抑制海马神经干细胞的增殖和分化，并损害成年期的神经认知功能。Notch1 信号通路可能与新生儿暴露于氯胺酮引起的成年期海马依赖性学习和记忆障碍有关。这些发现有助于进一步了解新生儿接触氯胺酮引起的神经毒性及其潜在机制。