The effects of the 15q11.2 BP1-BP2 copy number variant on white matter microstructure

Altered white matter structure has been consistently reported in neurodevelopmental disorders. A key question is whether genetic risk variants that are associated with neurodevelopmental disorders, are also associated with changes in white matter. The 15q11.2 BP1-BP2 copy number variant (CNV) is emerging as a recognised syndrome and has been associated with several neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia. The cytoplasmic FMR1 interacting protein 1 (CYFIP1), a gene in this region, is involved in two distinct complexes, known to regulate actin cytoskeleton dynamics and protein translation - mechanisms that are crucial in white matter dynamics. This thesis describes a translational project combining a diverse set of multidisciplinary experiments to investigate the effects of the 15q11.2 BP1BP2 CNV on white matter microstructure. In Chapters 3 and 4, using diffusion tensor imaging (DTI) methods, I demonstrate a link between 15q11.2 BP1-BP2 CNV dosage and altered white matter microstructure in human carriers, where bidirectional CNV dosage leads to opposite changes in white matter measures. In Chapters 5, 6 and 7, using a novel Cyfip1 haploinsufficiency rat model to model the low dosage of CYFIP1 in 15q11.2 BP1-BP2 deletion carriers, I investigate how this gene could contribute to the phenotype seen in Chapters 3 and 4. Combining DTI, histology and in vitro methods, I report that Cyfip1 haploinsufficiency leads to thinning of the myelin sheath in the corpus callosum, and suggest that these changes are caused by abnormal mechanisms involving myelin basic protein distribution in mature oligodendrocytes. In conclusion, these results show that variations at the 15q11.2 BP1-BP2 chromosomal region lead to white matter abnormalities, and suggest that Cyfip1 influences myelination in the central nervous system in a rat model, providing an insight into a possible contribution made by low dosage of CYFIP1 to 15q11.2 BP1-BP2 deletion associated phenotypes