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

Ana I. Silva, Josephine E. Haddon, Yasir Ahmed Syed, Simon Trent, Tzu-Ching E. Lin, Yateen Patel, Jenny Carter, Niels Haan, Robert C. Honey, Trevor Humby, Yaniv Assaf, Michael J. Owen, David E. J. Linden, Jeremy Hall () and Lawrence S. Wilkinson ()
Additional contact information
Ana I. Silva: MRC Centre for Neuropsychiatric Genetics and Genomics
Josephine E. Haddon: MRC Centre for Neuropsychiatric Genetics and Genomics
Yasir Ahmed Syed: MRC Centre for Neuropsychiatric Genetics and Genomics
Simon Trent: MRC Centre for Neuropsychiatric Genetics and Genomics
Tzu-Ching E. Lin: MRC Centre for Neuropsychiatric Genetics and Genomics
Yateen Patel: MRC Centre for Neuropsychiatric Genetics and Genomics
Jenny Carter: MRC Centre for Neuropsychiatric Genetics and Genomics
Niels Haan: MRC Centre for Neuropsychiatric Genetics and Genomics
Robert C. Honey: Cardiff University
Trevor Humby: MRC Centre for Neuropsychiatric Genetics and Genomics
Yaniv Assaf: Tel-Aviv University, Ramat Aviv
Michael J. Owen: MRC Centre for Neuropsychiatric Genetics and Genomics
David E. J. Linden: MRC Centre for Neuropsychiatric Genetics and Genomics
Jeremy Hall: MRC Centre for Neuropsychiatric Genetics and Genomics
Lawrence S. Wilkinson: MRC Centre for Neuropsychiatric Genetics and Genomics

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11119-7

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