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Down syndrome patients causes improper development of neurons

2023 Apr 21, 17:25,

 The University of Michigan researchers discovered that an extra copy of a gene in Down syndrome patients promotes abnormal neuron growth in mice.

The gene in question, known as Down syndrome cell adhesion molecule, or DSCAM, has also been linked to autism spectrum diseases, bipolar disorder, and intractable epilepsy.

Down syndrome is caused by an extra copy of chromosome 21, also known as trisomy 21. However, because this chromosome contains over 200 genes, including DSCAM, establishing which gene or genes on the chromosome contribute to which specific symptoms of the condition is a big issue in Down syndrome research and therapy.

"The ideal path for treatment would be to identify the gene that causes a medical condition, and then target this gene or other genes that it works with to treat that aspect of Down syndrome," said Bing Ye, a neuroscientist at the U-M Life Sciences Institute and lead author of the study.

"But for Down syndrome, we can't just sequence patient genomes to find such genes, because we'd find at least 200 different genes that are changed. We have to dig deeper to figure out which of those genes causes which problem."

For this work, researchers turn to animal models of Down syndrome. By studying mice that have a third copy of the mouse equivalent of chromosome 21, Ye and his team have now demonstrated how an extra copy of DSCAM contributes to neuronal dysfunction. Their findings are described in an April 20 study in PLOS Biology.

ach neuron has two sets of branches that extend out from the cell center: dendrites, which receive signals from other nerve cells, and axons, which send signals to other neurons. Ye and colleagues previously determined that an overabundance of the protein encoded by DSCAM can cause overgrowth of axons in fruit fly neurons.

Guided by their research in flies, the team has now found that a third copy of DSCAM in mice leads to increased axon growth and neuronal connections (called synapses) in the types of neurons that put the brakes on other neurons' activities. These changes lead to greater inhibition of other neurons in the cerebral cortex--a part of the brain that is involved in sensation, cognition and behavior.

"It's known that these inhibitory synapses are changed in Down syndrome mouse models, but the gene that underlies this change is unknown," said Ye, who is also a professor of cell and developmental biology at the U-M Medical School. "We show here that the extra copy of DSCAM is the primary cause of the excessive inhibitory synapses in the cerebral cortex."

The team demonstrated that in mice that had only two copies of DSCAM, but three copies of the other genes that are similar to human chromosome 21 genes, axon growth appeared normal.

"These results are striking because, although these mice have an extra copy of about a hundred genes, normalization of this single gene, DSCAM, rescues normal inhibitory synaptic function," said Paul Jenkins, assistant professor of pharmacology and psychiatry at the Medical School and co-corresponding author of the study.

"This suggests that modulation of DSCAM expression levels could be a viable therapeutic strategy for repairing synaptic deficits seen in Down syndrome. In addition, given that alterations of DSCAM levels are associated with other brain disorders like autism spectrum disorder and bipolar disorder, these results shed insight into potential mechanisms underlying other human diseases." 


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