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- Title
Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility.
- Authors
Trent, Simon; Lin, Tzu-Ching E.; Patel, Yateen; Carter, Jenny; Haan, Niels; Owen, Michael J.; Hall, Jeremy; Silva, Ana I.; Linden, David E. J.; Haddon, Josephine E.; Wilkinson, Lawrence S.; Humby, Trevor; Ahmed Syed, Yasir; Honey, Robert C.; Assaf, Yaniv
- 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. People with a genetic deletion of the 15q11.2 locus are at increased risk for psychiatric disorders and white matter disturbances, but the gene(s) responsible are unclear. Here, the authors show that low dosage of CYFIP1, present in the human 15q11.2 region, alters white matter structure and cognition in rats.
- Subjects
OLIGODENDROGLIA; RIGIDITY (Psychology); MYELIN; WHITE matter (Nerve tissue); TRANSMISSION electron microscopy
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-11119-7