New Improved Mouse Model of Down Syndrome Developed

The “gold standard” mouse model of Down syndrome, Ts65Dn, has been found to be inferior to a new genetic animal model of Down syndrome. In a study published today in Biological Psychiatry, the new mouse model, Ts66Yah, was shown to have memory difficulties and behavior traits, but the symptoms were not as severe as seen with the previous mouse model.

“A mouse model that more precisely captures the genetics of Down syndrome has important implications for human clinical trials that aim to improve cognition,” said Diana W. Bianchi, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and senior author of the study. 

Ts65Dn has been considered the standard for Down syndrome research and used in preclinical studies for nearly 30 years. Its genome contains 45 extra genes that are irrelevant to human Down syndrome, a byproduct of how the model was developed. Humans and mice have very similar genomes, but the chromosomes that make up those genomes do not precisely align across those two species. For example, many of the genes found on human chromosome 21 are found on mouse chromosomes 16 and 17. Ts65Dn has an additional region of mouse chromosome 17 that contains 45 extra genes not found on human chromosome 21. How these 45 extra genes affect the brain and behavior of the previous Ts65Dn mice has not been investigated until now. 

To create an enhanced mouse model of Down syndrome, researchers at the University of Strasbourg, France, removed these extra 45 genes using CRISPR gene-editing technology. Dr. Bianchi’s group then compared the two mouse models and found that the extra 45 genes in the previous mouse model were affecting brain development and contributed to more severe difficulties with motor skills, communication and memory. 

“There are considerable effects of these extra genes on mouse brain development and behavior,” said Faycal Guedj, first author of the study. “What was previously thought as the best mouse model of Down syndrome has traits derived from genes that are not relevant to human chromosome 21.” 

With this new and improved mouse model, Dr. Bianchi’s group hopes to develop more precise treatments for improving cognition in people with Down syndrome.