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Neonatal Anesthesia by Ketamine in Neonatal Rats Inhibits the Proliferation and Differentiation of Hippocampal Neural Stem Cells and Decreases Neurocognitive Function in Adulthood via Inhibition of the Notch1 Signaling Pathway

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Abstract

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.

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Data availability

All data during this study are included in the supplementary information file.

The experimental protocol was approved by the Institutional Animal Care and Ethics Committee of Xuzhou Medical University.

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Funding

This work was supported by the National Natural Science Foundation of China (81171013, 81901100), Jiangsu Province Special Program for Young Medical Talent (QNRC2016587), and the Natural Science Foundation of Jiangsu Province (BK20191464).

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Author notes

  1. He Huang and Chao Zhao contributed equally to this work

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China

    He Huang

  2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, People’s Republic of China

    Chao Zhao, Qiang Liu, Yi-Man Sun, Chen Chen, Hui Huang & Yu-Qing Wu

  3. Department of Anesthesiology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China

    Qian Hu

  4. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Tongshan Road 209, Xuzhou, 221004, People’s Republic of China

    Cheng-Hua Zhou

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  1. He Huang
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  2. Chao Zhao
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  3. Qian Hu
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  4. Qiang Liu
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Contributions

Conceived and designed the experiments: Yu-Qing Wu, He Huang, Chao Zhao, and Cheng-Hua Zhou; performed the experiments: He Huang, Chao Zhao, Qiang Liu, Yi-Man Sun, Chen Chen, and Hui Huang; data analysis and interpretation: Qian Hu, He Huang, and Yu-Qing Wu; manuscript preparation: He Huang and Yu-Qing Wu.

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Correspondence to Cheng-Hua Zhou or Yu-Qing Wu.

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Huang, H., Zhao, C., Hu, Q. et al. Neonatal Anesthesia by Ketamine in Neonatal Rats Inhibits the Proliferation and Differentiation of Hippocampal Neural Stem Cells and Decreases Neurocognitive Function in Adulthood via Inhibition of the Notch1 Signaling Pathway. Mol Neurobiol 58, 6272–6289 (2021). https://doi.org/10.1007/s12035-021-02550-3

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