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

Cyfip1+/- rats show extensive white matter changes, most pronounced in the corpus callosum.

“Similar observation using diffusion tensor imaging, showed extensive white matter changes in Cyfip1+/- rats, which were most pronounced in the corpus callosum32.”

A novel rat model haploinsufficient for Cyfip1 shows impaired reversal of visual discrimination in a touchscreen task.

“recent work has shown impaired reversal of visual discrimination in a touchscreen task in a novel rat model haploinsufficient for Cyfip1 [11].”

These sample sizes were utilised on the basis of previous published research and pilot studies.

“These sample sizes were utilised on the basis of previous published research [11, 44, 45] and pilot studies.”

Previous studies in Cyfip1 haploinsufficient animal models as well as 15q11.2 deletion CNV carriers have all reported marked changes to white matter in corpus callosum microstructure.

“Previous studies, in Cyfip1 haploinsufficient animal models as well as 15q11.2 deletion CNV carriers have all reported marked changes to white matter in corpus callosum microstructure [11–13].”

Previous research has reported changes to white matter in the low dosage Cyfip1 rat model, most prominently in corpus callosum.

“Previous research has reported changes to white matter in the low dosage Cyfip1 rat model, most prominently in corpus callosum [11]”

The Cyfip1 rat model was created using CRISPR-Cas9 targeting, implementing a 4 base-pair deletion in exon 7 of CYFIP1 on one chromosome, causing a premature stop codon leading to reduced CYFIP1 mRNA and protein in the brain.

“The Cyfip1 rat model was created by Cardiff University in collaboration with Horizon Discovery (St Louis, USA) using CRISPR–Cas9 targeting. CRISPR/Cas9 engineering of exon 7 implemented a 4 base-pair deletion in DNA of the CYFIP1 gene on one of the chromosomes, causing a premature stop codon leading to reduced CYFIP1 mRNA and CYFIP1 protein in the brain, mimicking the human situation in the 15q11.”

The Cyfip1 rat model recapitulates the low CYFIP1 dosage caused by 15q11.2 CNV deletions in patients.

“from a novel line designed to recapitulate the low CYFIP1 dosage caused by 15q11.2 CNV deletions in patients.”

In the Cyfip1 rat model, white matter changes have been linked to thinning of the myelin sheath on axons, independent of changes in the number or diameter of axons.

“In the rat model, these changes in white matter have been linked to thinning of the myelin sheath on axons, independent of changes in the number or diameter of axons [11].”

Reversal learning is sensitive to reductions of Cyfip1 in the rat.

“Hippocampal neurogenesis-mediated inhibition has been proposed as a mechanism to reduce memory interference—enabling cognitive flexibility in tasks such as reversal learning [76], which we have previously shown is sensitive to reductions of Cyfip1 in the rat [11].”

Changes in callosal white matter microstructure showing reduced myelination of nerve fibres previously reported in Cyfip1+/− rats may differentially constrain information transfer to and from the accumbens, resulting in the dysfunctional connectivity observed in this current study.

“Hence the changes in callosal white matter microstructure showing reduced myelination of nerve fibres previously reported in Cyfip1+/− rats [11] may differentially constrain information transfer to and from the accumbens, resulting in the dysfunctional connectivity observed in this current study.”

Some Cyfip1+/− rats were able to complete a reversal learning task in which performance to criteria rather than number of sessions of training dictated how long animals were trained for.

“For example, some Cyfip1+/− were able to complete a reversal learning task in which performance to criteria rather than number of sessions of training dictated how long animals were trained for [11].”

Extensive white matter changes, including thinning of the myelin sheath in the corpus callosum of rats or mice with haploinsufficiency of Cyfip1, have been observed, suggesting a potential contribution of myelination defects to the increased risk of psychiatric disorders observed in individuals with a 15q11.2 copy number deletion.

“Extensive white matter changes, including thinning of the myelin sheath in the corpus callosum of rats or mice with haploinsufficiency of Cyfip1, have been observed, suggesting a potential contribution of myelination defects to the increased risk of psychiatric disorders observed in individuals with a 15q11.2 copy number deletion79,80.”