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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.
Highlights
The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown
Group comparisons were carried out using Tract-Based Spatial Statistics (TBSS)[17] available in FMRIB Software Library (FSL), with a randomise function allowing voxel-wise nonparametric permutation analysis of the diffusion tensor imaging (DTI) maps projected onto a whole brain white matter skeleton (Supplementary Fig. 1)
The randomise function was used with the threshold-free cluster enhancement (TFCE)[18], generating cluster-size statistics based on 1000 random permutations
Summary
The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. The deletion contains four genes: non-imprinted in Prader-Willi/Angelman syndrome 1 gene (NIPA1), non-imprinted in Prader-Willi/Angelman syndrome 2 gene (NIPA2), CYFIP1 and tubulin gamma complex associated protein 5 gene (TUBGCP5)[3] Whilst all these genes are expressed in the brain and may be of potential relevance to psychopathology, CYFIP1 haploinsufficiency is considered to be a likely significant contributor to the 15q11.2 BP1-BP2 psychiatric phenotype due to its known involvement in a number of key brain plasticity-related functions. These include alterations in dendritic spine morphology and branching, mediated by interactions in two distinct complexes: the WAVE regulatory complex to modulate ARP2/3 dependent actin cytoskeleton dynamics, and CYFIP1-eIF4E complex to suppress protein translation at the synapse through interactions with fragile X mental retardation 1 protein (FMRP), the gene product of FMR14. The Wiskott-Aldrich Syndrome protein family member 1 (WAVE1) and the integrin-linked kinase (ILK) regulate oligodendrocyte differentiation and axon ensheathment[12,13], while the Arp2/3 complex, a key actin nucleator, is required for initiation of myelination[11], and Rho GTPases Cdc[42] and Rac[1] regulate myelin sheath formation[14]
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