Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility

Silva, Ana I.; Haddon, Josephine E.; Ahmed Syed, Yasir; Trent, Simon; Lin, Tzu-Ching E.; Patel, Yateen; Carter, Jenny; Haan, Niels; Honey, Robert C.; Humby, Trevor; Assaf, Yaniv; Owen, Michael J.; Linden, David E.J.; Hall, Jeremy; Wilkinson, Lawrence S.

Abstract

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

Citation

Silva, A. I., Haddon, J. E., Ahmed Syed, Y., Trent, S., Lin, T. E., Patel, Y., …Wilkinson, L. S. (2019). Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility. Nature communications, 10, Article 3455. https://doi.org/10.1038/s41467-019-11119-7

• Journal Article Type: Article
• Acceptance Date: Jun 20, 2019
• Publication Date: Aug 1, 2019
• Journal: Nature Communications
• Print ISSN: 2041-1723
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Article Number: 3455
• DOI: https://doi.org/10.1038/s41467-019-11119-7
• Keywords: Cyfip1 haploinsufficient, myelin thinning, abnormal oligodendrocytes, behavioural inflexibility.
• Publisher URL: https://www.nature.com/articles/s41467-019-11119-7