Myelin loss might clarify how autism-linked DNA deletion impacts cognition | Spectrum
Missing myelin: Clearing TBX1 in mice decreases the amount of myelin around axons in several areas of the white matter of the brain.
Courtesy of Hiroi Nonaka
Mice lacking a copy of TBX1, a gene in the autism-linked 22q11.2 chromosomal region, are producing too little myelin – the fatty insulation that surrounds neurons – and performing poorly on tasks that measure cognitive speed, according to a new study .
The paper, published Nov. 5 in Molecular Psychiatry, may provide insight into the mechanisms underlying impaired cognitive function in some people with a 22q11.2 deletion and possibly other copy number variants (CNVs).
“The myelin changes could potentially turn out to be a shared neural deficit that mediates cognitive changes in many cases of CNV,” says lead researcher Noboru Hiroi, professor of pharmacology at the University of Texas Health Science Center at San Antonio.
Neural axons – the projections that conduct nerve impulses – are coated with myelin, which is used to speed up electrical transmission. Previous research has shown that the brains of autistic people and several mouse models of autism have myelin disorders.
These connecting fibers are the “highways of the brain,” says Valerie Bolivar, a researcher at the Wadsworth Center of the New York State Department of Health in Albany. “If the motorway doesn’t work, you won’t be able to get your goods from one place to another so quickly.”
Slow mice:
TBX1 codes for a protein that regulates the expression of other genes during brain development. Deleting a copy of TBX1 leads to social and communicative deficits in mice, according to previous studies by Hiroi’s team.
In the new study, the researchers mapped the brains of the TBX1 mice and found significant myelin changes only in the fimbriae, a bundle of nerve fibers in the hippocampus – a critical structure for learning and memory. Microscopic analyzes showed that large and medium axons in the fimbriae in the mutant mice had abnormally low levels of myelin.
This region of the brain showed decreased expression of NG2, a gene that the brain needs to produce the precursors of oligodendrocytes, the cells that produce myelin. Another zone of the fimbriae also produced fewer oligodendrocytes.
The TBX1 mice stalled several behavioral tests. They were worse than their wild littermates at navigating their environment in the Morris water maze, which tests spatial memory and is based on an intact hippocampus. And they worked slower on an attention set shifting task, where attention was shifted from one stimulus to another in order to measure attention and cognitive flexibility.
“When myelin is affected, it can affect the efficiency of the entire brain,” says Carrie Bearden, a professor of psychiatry and bio-behavioral science at the University of California, Los Angeles, who was not involved in the study. “What it really affects in humans is the processing speed.”
Understanding how CNVs can affect certain cognitive functions is key to developing treatments.
“We have the starting point for precision medicine. You can try targeting myelin in the fimbriae rather than the entire brain, ”says Hiroi.
However, researchers caution that the observed changes in myelination in mice do not necessarily match what is going on in the human brain and that the results need to be validated in humans.
“The degree of myelination in a mouse brain is completely different than in humans,” says Bearden.
In the future, the researchers plan to investigate whether their results can be transferred to other CNVs.
Cite this article: https://doi.org/10.53053/ZFYM6324
