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Decreased number and increased volume with mitochondrial enlargement of cerebellar synaptic terminals in a mouse model of chronic demyelination

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Abstract

Impaired nerve conduction, axonal degeneration, and synaptic alterations contribute to neurological disabilities in inflammatory demyelinating diseases. Cerebellar dysfunction is associated with demyelinating disorders, but the alterations of axon terminals in cerebellar gray matter during chronic demyelination are still unclear. We analyzed the morphological and ultrastructural changes of climbing fiber terminals in a mouse model of hereditary chronic demyelination. Three-dimensional ultrastructural analyses using serial block-face scanning electron microscopy and immunostaining for synaptic markers were performed in a demyelination mouse model caused by extra copies of myelin gene (PLP4e). At 1 month old, many myelinated axons were observed in PLP4e and wild-type mice, but demyelinated axons and axons with abnormally thin myelin were prominent in PLP4e mice at 5 months old. The density of climbing fiber terminals was significantly reduced in PLP4e mice at 5 months old. Reconstruction of climbing fiber terminals revealed that PLP4e climbing fibers had increased varicosity volume and enlarged mitochondria in the varicosities at 5-month-old mice. These results suggest that chronic demyelination is associated with alterations and loss of climbing fiber terminals in the cerebellar cortex, and that synaptic changes may contribute to cerebellar phenotypes observed in hereditary demyelinating disorders.

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Acknowledgements

We thank Drs. M Yuzaki, A Kakegawa (Keio University) and M Watanabe (Hokkaido University) for helpful discussion and support. This work is partly supported by JSPS KAKENHI Grant number 16K12345 (to N.O.) and Grants-in-Aid for Scientific Research on Innovative Areas “glial assembly” (no. 25117005 to K.I.), and Research Grant from National Center of Neurology and Psychiatry (no. 30-5 to N.O.) and Novartis Pharma, Cooperative Research Program of “Network Joint Research Center for Materials and Devices” and Cooperative Study Programs of National Institute for Physiological Sciences (to N.O.). We would like to thank Setsuro Fujii Memorial, Osaka Foundation for Promotion of Fundamental Medical Research for providing the support.

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Authors and Affiliations

  1. Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan

    Huy Bang Nguyen, Yang Sui, Truc Quynh Thai, Kazuhiro Ikenaka & Nobuhiko Ohno

  2. Department of Anatomy and Structural Biology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan

    Huy Bang Nguyen, Yang Sui, Truc Quynh Thai & Toshiyuki Oda

  3. Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan

    Nobuhiko Ohno

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Nguyen, H.B., Sui, Y., Thai, T.Q. et al. Decreased number and increased volume with mitochondrial enlargement of cerebellar synaptic terminals in a mouse model of chronic demyelination. Med Mol Morphol 51, 208–216 (2018). https://doi.org/10.1007/s00795-018-0193-z

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