DOWN'S DETERMINANT: Down's syndrome results when an extra copy of all or part of chromosome 21 is inherited. White arrows indicate three copies of chromosome 21 in this image of all the chromosomes from a single cell. Image: NIH
Down's syndrome (DS) is an incurable, heritable disorder affecting an estimated 400,000 people in the U.S. It is characterized by impaired cognitive ability and abnormal physical growth. Whereas scientists have long known that DS is caused by inheriting an extra copy of all or part of chromosome 21, the underlying cause of the brain defects common in Down's patients has not been fully gleaned.
Now, a collaborative team of scientists working with a mouse model of DS has discovered that just two genes are responsible for the majority of the brain abnormalities present in their animals. The scientists hope that their findings will help scientists understand brain defects in humans with the disorder as well as aid in the development of drugs to treat the cognitive impairment in Down's patients.
Previous studies suggest that brain defects in DS mice occur very early, while the mice are still developing embryos. These defects result from abnormalities in how brain neurons communicate with each other—either via excitatory signals, which stimulate other neurons to communicate, or inhibitory signals, which act to prevent other neurons from firing. During embryonic development, the proper ratio of excitatory and inhibitory neurons is established for optimal brain function. These electrical circuits are the basis for memory formation and learning.
Human chromosome 21 has more than 300 genes on it. Some of the features of DS—including cognitive deficits, heart defects, gastrointestinal problems and poor muscle tone—could therefore result from having either an additional copy of a single gene on chromosome 21; combinations of extra genes; or from the effects some redundant genes may exert on other chromosomes' genes. This complexity has significantly slowed the pace of researchers' attempts to understand the genetic basis of how such a diverse array of symptoms and abnormalities arise.
In the new study led by Tarik Haydar, then at the Children's National Medical Center in Washington, D.C., the scientists sought to determine which of the extra genes in the DS mice are responsible for brain defects. (Haydar is currently a professor of anatomy and neurobiology at Boston University School of Medicine.) Their results were published online July 18 in Nature Neuroscience (Scientific American is a part of Nature Publishing Group).
First, the scientists found abnormal proportions of excitatory and inhibitory neurons in the brains of the embryonic DS mice, with a much higher quantity of the inhibitory cells. Then they looked over the list of extra genes present in the DS mice and homed in on Olig1 and Olig2, which are known from previous studies to program the developing brain to produce inhibitory neurons. They then engineered a generation of DS mice to have the normal genetic dosage of these genes. They found that simply eliminating the superfluous copies of Olig1 and Olig2 prevented the brain defects and restored normal communication among the neurons.
"This is an extremely elegant set of experiments, which are very difficult to do," says Roger Reeves, professor of physiology at Johns Hopkins University School of Medicine who studies mechanisms of gene action in Down's syndrome and was not involved in the study. The results "very much expand our understanding of just how these imbalances come to be in the first place, and demonstrates the specific role of [these genes] in this imbalance," Reeves says. He adds that the findings have important implications for several different drugs designed to ameliorate cognitive deficits in DS that are currently making their way to clinical trials.