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Nat Commun. 2019 Aug 1;10(1):3455. doi: 10.1038/s41467-019-11119-7.

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

Silva AI1,2,3, Haddon JE1,2,4, Ahmed Syed Y1,5, Trent S1,2, Lin TE1,2, Patel Y1,2, Carter J1,2, Haan N1,2, Honey RC4, Humby T1,4, Assaf Y6, Owen MJ1,2, Linden DEJ1,2,3,7, Hall J8,9, Wilkinson LS10,11,12.

Author information

1
Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cathays, Cardiff, CF24 4HQ, UK.
2
Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK.
3
Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, UK.
4
School of Psychology, Cardiff University, Cardiff, Park Place, CF10 3AT, UK.
5
School of Bioscience, The Sir Martin Evans Building, Museum Ave, Cardiff, CF10 3AX, UK.
6
Department of Neurobiology, Tel-Aviv University, Ramat Aviv, 6997801, Tel-Aviv, Israel.
7
School of Mental Health and Neuroscience, Maastricht University, Maastricht, 6229 ER, The Netherlands.
8
Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cathays, Cardiff, CF24 4HQ, UK. Hallj10@cardiff.ac.uk.
9
Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK. Hallj10@cardiff.ac.uk.
10
Neuroscience and Mental Health Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Cathays, Cardiff, CF24 4HQ, UK. wilkinsonl@cardiff.ac.uk.
11
Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK. wilkinsonl@cardiff.ac.uk.
12
School of Psychology, Cardiff University, Cardiff, Park Place, CF10 3AT, UK. wilkinsonl@cardiff.ac.uk.

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.

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