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Midazolam Exposure Impedes Oligodendrocyte Development via the Translocator Protein and Impairs Myelination in Larval Zebrafish

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Abstract

Anesthetics are commonly used in various medical procedures. Accumulating evidence suggests that early-life anesthetics exposure in infants and children affects brain development, causing psychiatric and neurological disorders. However, the underlying mechanisms are poorly understood. Using zebrafish larvae as a model, we found that the proliferation and migration of oligodendrocyte progenitor cells (OPCs) were severely impaired by the exposure of midazolam (MDZ), an anesthetic widely used in pediatric surgery and intensive care medicine, leading to a reduction of oligodendroglial lineage cell in the dorsal spinal cord. This defect was mimicked by the bath application of translocator protein (TSPO) agonists and partially rescued by genetic downregulation of TSPO. Cell transplantation experiments showed that requirement of TSPO for MDZ-induced oligodendroglial lineage cell defects is cell-autonomous. Furthermore, transmission electron microscopy and in vivo electrophysiological recording experiments demonstrated that MDZ exposure caused axon hypomyelination and action potential propagation retardation, resulting in delayed behavior initiation. Thus, our findings reveal that MDZ affects oligodendroglial lineage cell development and myelination in young animals, raising the care about its clinic use in infants and children.

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The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Dr Bruce Appel at University of Colorado School of Medicine for providing the Tg(olig2:EGFP) transgenic zebrafish, Sox10:mRFP plasmid and anti-sox10 antibody.

Funding

This work was supported by the National Natural Science Foundation of China (grants no. 81200942, 81671058 and 81730031) and the Foundation of Shanghai Municipal Key Clinical Specialty (grant no. shslczdzk06901).

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Authors and Affiliations

  1. Department of Anesthesiology, Huashan Hospital, Fudan University, No. 12 Wu lu mu qi Road, Shanghai, 200040, China

    Daojie Xu, Bin Wang & Yingwei Wang

  2. Department of Anesthesiology, Xinhua Hospital, Medical School, Shanghai Jiaotong University, 1665 Kong-Jiang Road, Shanghai, 200092, China

    Bo Xu & Li Ning

  3. Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China

    Chen Yin, Xiaoquan Li & Jiulin Du

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  1. Daojie Xu
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Contributions

Daojie Xu designed, planned and performed the experiments, analyzed the data, and wrote the manuscript. Bin Wang performed DNA microinjection and assisted with cell transplantation experiments. Bo Xu performed immunohistochemistry and assisted with time-lapse imaging experiments. Chen Yin performed in vivo electrophysiological recording. Li Ning assisted with transmission electron microscopy and drug treatment experiments. Xiaoquan Li assisted with C-start escape behavior test. Jiulin Du oversaw all research phases and contributed to writing the manuscript. Yingwei Wang coordinated and supervised the project and wrote the manuscript.

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Correspondence to Yingwei Wang.

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Xu, D., Wang, B., Xu, B. et al. Midazolam Exposure Impedes Oligodendrocyte Development via the Translocator Protein and Impairs Myelination in Larval Zebrafish. Mol Neurobiol 59, 93–106 (2022). https://doi.org/10.1007/s12035-021-02559-8

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