Published Research: Microcephaly in AS Mice
See the paper by Matthew Judson in The Journal of Neuroscience.
Summary
Many individuals with Angelman syndrome (AS) have microcephaly—a smaller head and brain size—than typically developing individuals. This microcephaly is not present at birth, but becomes evident sometime during the first 18 months of life, indicating a problem with brain growth. During this early phase of development, the brain typically grows very quickly and must develop in a precise manner to support normal brain functions. In AS, the brain grows more slowly, and this correlates with developmental delay, impaired motor function, and EEG abnormalities. The ASF-funded research team, led by Ben Philpot, Ph.D., studied microcephaly in AS mice and sought to determine the cause of reduced brain size in the mice. The results were published in the August 2nd issue of The Journal of Neuroscience.
The team examined the brain growth of AS mice during early development and found that they develop microcephaly after birth. Although newborn AS mice have the same sized brains as their neuro-typical counterparts, the brains of AS mice grow more slowly, and are thus smaller than their neuro-typical littermates by the time they are juveniles. As with individuals with AS, this microcephaly persists into adulthood. Notably, Philpot’s group showed that changes in the amount of white matter accounted for most of the microcephaly in AS mice. White matter contains bundles of axons, which are the long, slender portions of neurons that transmit electrical signals to other neurons or muscles. Axons are coated with a substance called myelin, which acts to insulate the electrical activity of axons. Philpot and colleagues found that although the amount of myelin was normal in adult AS mice, the axons in AS mice were smaller in diameter than the mice without AS. These smaller axons correlated with deficits in nerve conduction in the AS mice. Future research will help determine exactly how the axon diameter deficit in AS mice arises during development, whether it might be related to delays in myelination, and how it could contribute to behavioral phenotypes.
White matter deficits have been previously reported in individuals with AS. The ASF recently funded a collaborative group including Drs. Ben Philpot, Mark Shen, Heather Hazlett, and Ron Thibert to study this process in children and young adults with AS. Preliminary data from this work was presented at the Angelman Syndrome Foundation’s 2017 Research Symposium. More work in this important area of brain research is needed to determine if the white matter deficits observed in individuals with AS are caused by changes in axon diameter, as predicted by Philpot’s recent findings in AS mice. Importantly, if the extent of white matter structural deficits proves to correlate with the severity of impairments in nerve conduction and motor skills performance in individuals with AS, then measurement of white matter may serve as a helpful biomarker to gauge responsiveness to a potential treatment.