Integrity of White Matter is Compromised in Mice with Hyaluronan Deficiency

Ang D. Sherpa, David N. Guilfoyle, Aditi A. Naik, Jasmina Isakovic, Fumitoshi Irie, Yu Yamaguchi, Jan Hrabe, Chiye Aoki, Sabina Hrabetova

Research output: Contribution to journalArticle

Abstract

Brain white matter is the means of efficient signal propagation in brain and its dysfunction is associated with many neurological disorders. We studied the effect of hyaluronan deficiency on the integrity of myelin in murine corpus callosum. Conditional knockout mice lacking the hyaluronan synthase 2 were compared with control mice. Ultrastructural analysis by electron microscopy revealed a higher proportion of myelin lamellae intruding into axons of knockout mice, along with significantly slimmer axons (excluding myelin sheath thickness), lower g-ratios, and frequent loosening of the myelin wrappings, even though the myelin thickness was similar across the genotypes. Analysis of extracellular diffusion of a small marker molecule tetramethylammonium (74 MW) in brain slices prepared from corpus callosum showed that the extracellular space volume increased significantly in the knockout animals. Despite this vastly enlarged volume, extracellular diffusion rates were significantly reduced, indicating that the compromised myelin wrappings expose more complex geometric structure than the healthy ones. This finding was confirmed in vivo by diffusion-weighted magnetic resonance imaging. Magnetic resonance spectroscopy suggested that water was released from within the myelin sheaths. Our results indicate that hyaluronan is essential for the correct formation of tight myelin wrappings around the axons in white matter.

Original languageEnglish (US)
Pages (from-to)53-67
Number of pages15
JournalNeurochemical Research
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • Axon
  • Diffusion
  • Electron microscopy
  • Hyaluronan
  • Magnetic resonance
  • Myelin

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Sherpa, A. D., Guilfoyle, D. N., Naik, A. A., Isakovic, J., Irie, F., Yamaguchi, Y., Hrabe, J., Aoki, C., & Hrabetova, S. (2020). Integrity of White Matter is Compromised in Mice with Hyaluronan Deficiency. Neurochemical Research, 45(1), 53-67. https://doi.org/10.1007/s11064-019-02819-z