Experimental compound reverses Down syndrome-like learning deficits in mice

Researchers at Johns Hopkins and the National Institutes of Health have identified a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition.

In their experiments, detailed in a report in Wednesday's issue of Science Translational Medicine, the single-dose treatment appears to enable the cerebellum of the rodents' brains to grow to a normal size. The scientists caution that use of the compound—a small molecule known as a sonic hedgehog pathway agonist—has not been proven safe to try in people with Down syndrome, but say their experiments hold promise for developing similar compounds.

"Most people with Down syndrome have a cerebellum that's about 60 percent of the normal size," says Roger Reeves, a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. "We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum's growth, and it worked beautifully. What we didn't expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum."

Reeves has devoted his career to studying Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this "trisomy," people with Down syndrome have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features, and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a formidable challenge, Reeves says.

For their current experiments, Reeves and his colleagues used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21. The mice have many characteristics similar to those of people with Down syndrome, including relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. In the case of the mice, the latter was tested by tracking how readily the animals located a platform while swimming in a water maze.

The researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development using a compound known as a sonic hedgehog pathway agonist. The compound was injected into the Down syndrome-like mice just once, on the day of birth, while their cerebellums were still developing.

"We were able to completely normalize growth of the cerebellum through adulthood with that single injection," Reeves says.

But the research team went beyond measuring the cerebellums, looking for changes in behavior, too. "Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could," Reeves says. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test.

Reeves says further research is needed to learn why the treatment works, because certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the treatment.

As for the compound's potential to become a human drug, the problem, Reeves says, is that altering an important biological chain of events like sonic hedgehog would likely have many unintended effects throughout the body, such as raising the risk of cancer by triggering inappropriate growth. But now that the team has seen the potential of this strategy, they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum.

"Down syndrome is very complex, and nobody thinks there's going to be a silver bullet that normalizes cognition," Reeves said. "Multiple approaches will be needed."