People carrying a heterozygous deletion of the 15q11.2 locus between break point 1 (BP1) and BP2 have a 2–4-fold increase in likelihood of developing brain disorders such as autism spectrum disorder (ASD), schizophrenia and epilepsy. These individuals also show functional connectivity defects and white matter changes in areas such as the corpus callosum — a key axonal commissure required for bilateral functional connectivity. In addition, >40% of individuals with 15q11.2 BP1–BP2 haploinsufficiency show delayed development of motor skills, and motor coordination and balance deficits have been described in people with ASD. Of the four genes contained in the 15q11.2 BP1–BP2 region, cytoplasmic FMRP-interacting protein 1 (CYFIP1) is likely to be the main mediator in particular because of its involvement in actin cytoskeleton dynamics (the process of myelination involves actin remodelling) and regulating protein synthesis. The mechanisms underlying white matter changes in people with 15q11.2 BP1–BP2 haploinsufficiency are poorly understood, but two recent papers show that CYFIP1 plays a crucial role.

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Silva et al. used CRISPR–Cas9 technology to develop a rat model containing a heterozygous deletion of Cyfip1 (Cyfip1+/- rats). Whole-brain analysis of white matter structure in these rats using diffusion tensor imaging (DTI) revealed extensive differences in white matter microstructure compared with wild-type controls. Fractional anisotropy (a proxy for white matter integrity) was reduced in most brain areas including the corpus callosum. Ultrastructural analysis of the corpus callosum of Cyfip1+/- rats using transmission electron microscopy showed reduced myelin thickness but no effect on axon density or calibre. Moreover, the corpus callosum of Cyfip1+/- rats contained fewer oligodendrocyte lineage cells and mature oligodendrocytes (which produce myelin) than that of wild-type animals.

Next, the authors looked at expression of the mature oligodendrocyte marker myelin basic protein (MBP). Cyfip1+/- rats had lower MBP expression in the corpus callosum than did wild-type rats. Cultured oligodendrocytes taken from Cyfip1+/- rats showed MBP staining localized in the soma region. By contrast, MBP distribution in wild-type oligodendrocytes showed widespread distribution through the cell, including in cell processes, a pattern that precedes myelination. These findings suggest that translocation of MBP within oligodendrocytes from Cyfip1+/- rats is compromised and this could underlie the myelin thinning observed in these rats.

Finally, to investigate effects on behavioural flexibility, the authors used an appetitive reversal learning task in which rats learned to associate one of two stimuli with a reward, which were later switched. Cyfip1+/- rats learned the first stimulus–reward association as well as wild-type animals, but showed deficits in their ability to relearn after the association had been switched to the other stimulus.

Domínguez-Iturza et al., using resting-state functional MRI in Cyfip1+/- mice, revealed functional connectivity deficits compared with controls. Specifically, Cyfip1+/- mice showed a general decrease in functional connectivity, particularly in bilateral connections between hemispheres (that is, corpus callosum-dependent) in areas such as somatosensory cortex.

The authors next analysed myelin structure in the corpus callosum using DTI and electron microscopy. Consistent with Silva et al., who used a rat model for CYFIP1 haploinsufficiency, Domínguez-Iturza et al. found in the Cyfip1+/- mouse model a reduced fractional anisotropy and reduced myelin thickness compared with wild-type animals.

Callosal myelination is required for efficient axonal transmission. The authors found that following stimulation of callosal axons that project to layer 2/3 cortex, synaptic plasticity was different in Cyfip1+/- mice compared with controls, indicating altered transmission through the corpus callosum in Cyfip1+/- mice.

Finally, the authors found that Cyfip1+/- mice showed impaired performance on the rotarod and ladder rung walking tests (indicative of impaired motor co-ordination). Cyfip1+/- mice scored worse in the texture novel object recognition test, which is thought to represent one of the ASD-like behaviours, and showed reduce pre-pulse inhibition, indicating reduced sensory–motor gating, defects of which are found in people with schizophrenia.

Together, these studies suggest that haploinsufficiency in Cyfip1 in rodents results in reduced myelin thickness in the corpus callosum, altered neurotransmission and behavioural deficits that have parallels to those observed in ASD and schizophrenia.