The first rat genetic model of Down syndrome offers a better understanding of the disease
Seeking better ways to test new therapies and further explore the impacts of the unique genetics associated with Down syndrome, researchers from Johns Hopkins Medicine and Tottori University in Japan have genetically engineered and characterized what the believed to be the first rat model of Down syndrome.
A report of their research appeared on January 24 in The American Journal of Human Genetics.
Scientists have long searched for ways to improve medical care for people with Down syndrome, especially those who suffer from the physical and mental challenges that characterize the disease. These include a higher risk of heart defects, gastrointestinal problems, and learning and memory difficulties.
Developing an animal model that shares these characteristics with human Down syndrome will allow us to more effectively test therapies, with higher chances of developing ones that may work in humans. »
Roger H. Reeves, Ph.D., Professor of Physiology, Johns Hopkins University School of Medicine
Basically, Down syndrome is the result of a so-called chromosomal “trisomy” or tripling. A typical human cell has 23 pairs of chromosomes, which contain genetic instructions that govern its internal functioning and how it interacts with the rest of the body. Down syndrome occurs when a person is born with a partial or full extra copy of the 21st chromosome, a condition called trisomy 21. The effects of this extra chromosome are widely expressed throughout the body and its impacts vary between individuals.
Like humans, rats do not randomly produce offspring with extra 21st chromosomes. So the researchers decided to perform a complicated feat of genetic engineering to generate rats with an extra chromosome 21.
The process involved transferring the 21st chromosome from human white blood cells to mouse cells, then to chicken cells, then to hamster cells and, finally, into a rat embryo.
With each transfer, the researchers made different genetic modifications, including the addition of a green glowing protein, which under ultraviolet light identified the rats with extra chromosome 21s.
Reeves and his team then assessed the cognition and physical characteristics of the genetically modified rats for traits associated with an extra 21st chromosome.
To test the rats’ learning and memory, for example, the researchers performed standardized maze tests with the genetically modified rats.
Rats with an extra 21st chromosome took longer to solve the maze than genetically typical rats. They also had a harder time remembering the maze solution when they were challenged to solve the same puzzle for four consecutive days.
Other cognitive tests showed that, overall, rats with an extra chromosome 21 were more anxious and hyperactive than rats without an extra chromosome. These findings are consistent with ratings of people with Down syndrome, who report having higher rates of anxiety, attention deficit disorder, and learning and memory impairment.
In anatomical studies, researchers also found that a brain structure called the cerebellum was significantly smaller in rats with an extra 21st chromosome. The cerebellum is central to essential body functions, including the processing of messages in the brain, and is much smaller in people with Down syndrome.
“There are already advances in the development of pharmaceuticals that help the cerebellum grow in mice,” says Reeves. “If we eventually translate this into medicine for humans, we may be able to help people with Down syndrome improve their learning and memory abilities.”
The distinct facial differences in people with Down syndrome — such as flatter faces, almond-shaped eyes and smaller heads — were also present in the rats. Although people cannot look at a rat and determine if its face is different from that of a typical rodent, a computer program can measure the differences. The skulls were scanned in a CT machine and the data added to a computer modeling program, which revealed the rats had shortened snouts. The bones making up these features in the rat skull match those in human skulls that make up the characteristic facial “flattening” in people with Down syndrome.
Finally, 17% of rats with an extra 21st chromosome had an abnormality of the heart ventricles similar to that diagnosed in up to 21% of children with Down syndrome.
The model will be distributed to researchers through the NIH-supported Rat Resource and Research Center at the University of Missouri and the National BioResource Project for the Rat in Japan.
Kazuki, Y. et al. (2022) A transchromosomal rat model with human chromosome 21 shows robust features of Down syndrome. The American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2021.12.015.