Researchers at the University of Michigan have discovered that an extra copy of a gene in patients with Down syndrome causes improper development of neurons in mice.
The gene in question, called the Down syndrome cell adhesion molecule, or DSCAM, is also implicated in other human neurological conditions, including autism spectrum disorders, bipolar disorder, and intractable epilepsy.
It is known that the cause of Down syndrome is an extra copy of chromosome 21, or trisomy 21. But because this chromosome contains more than 200 genes, including DSCAM, a major challenge in Down syndrome research and treatments is determine which gene or genes on the chromosome contribute to which specific symptoms of the syndrome.
“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 UM Life Sciences. Institute and lead author of the study.
“But for Down syndrome, we can’t just sequence the genomes of patients to find such genes, because we would find at least 200 different genes that are changed. We have to dig deeper to find out which of those genes causes which problem.”
For this work, the researchers turn to animal models of Down syndrome. By studying mice that have a mouse-equivalent third copy of chromosome 21, Ye and her team have now shown how an extra copy of DSCAM contributes to neuronal dysfunction. Their findings are described in an April 20 study in PLOS Biology.
Each neuron has two sets of branches that extend from the center of the cell: dendrites, which receive signals from other nerve cells, and axons, which send signals to other neurons. Ye and her colleagues previously determined that an overabundance of the DSCAM-encoded protein can cause axon overgrowth in fruit fly neurons.
Guided by their research in flies, the team has discovered that a third copy of DSCAM in mice leads to increased growth of axons and neuronal connections (called synapses) in the types of neurons that slow down the activities of other neurons. These changes lead to increased inhibition of other neurons in the cerebral cortex, a part of the brain that is involved in sensation, cognition, and behavior.
“These inhibitory synapses are known to change in mouse models of Down syndrome, but the gene underlying this change is unknown,” said Ye, who is also a professor of cell and developmental biology at the University of California School of Medicine. um. “We show here that the extra copy of DSCAM is the main cause of excessive inhibitory synapses in the cerebral cortex.”
The team showed 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 surprising because, although these mice have an extra copy of about a hundred genes, normalizing this single gene, DSCAM, rescues normal inhibitory synaptic function,” said Paul Jenkins, an assistant professor of pharmacology and psychiatry in the College of of Medicine and co-corresponding author of the study.
“This suggests that modulating DSCAM expression levels could be a viable therapeutic strategy to repair the synaptic deficits seen in Down syndrome. Furthermore, since alterations in DSCAM levels are associated with other brain disorders such as autism spectrum disorder and bipolar disorder, these results shed light on potential mechanisms underlying other human diseases.”
The research was supported by the National Institutes of Health, the Brain Research Foundation, and the University of Michigan. All procedures performed in mice were approved by the University of Michigan Institutional Animal Care and Use Committee and were performed in accordance with institutional guidelines.
Study authors are Hao Liu, René Caballero-Florán, Ty Hergenreder, Tao Yang, Jacob Hull, Geng Pan, Ruonan Li, Macy W. Veling, Lori Isom, Kenneth Kwan, Paul Jenkins, and Bing Ye of UM; Z. Josh Huang of Duke University; and Peter Fuerst of the University of Idaho.