Down syndrome: Single dose of drug boosts learning in mice

"We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum's growth, and it worked beautifully," says Roger Reeves. (Credit: iStockphoto)

An experimental compound dramatically bolsters learning and memory when given to newborn mice with a condition similar to Down syndrome.

One dose on the rodents’ day of birth appears to enable the cerebellum of the rodents’ brains to grow to normal size, researchers report.

The compound, a small molecule known as a sonic hedgehog pathway agonist, has not been proven safe to try in people, but the experiments hold promise for developing Down syndrome drugs based on it, scientists say.


“Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Reeves, professor of genetic medicine at 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,” Reeves says, “were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.”

Down syndrome is 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 more than 300 genes housed on that chromosome. That 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 the study, published in the journal Science Translational Medicine, researchers used mice 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. (This was tested by tracking how readily the mice located a platform while swimming in a so-called water maze.)

Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound—a sonic hedgehog pathway agonist—that could do just that.

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. 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.

Further research is needed to learn why exactly the treatment works, because cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment.

One possibility is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus.

No silver bullet

As for the compound’s potential to become a human drug, the problem, 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, Reeves says they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum.

Even if his team succeeds in developing a clinically useful drug, however, it wouldn’t constitute a “cure” for the learning and memory-related effects of Down syndrome.

“Down syndrome is very complex, and nobody thinks there’s going to be a silver bullet that normalizes cognition,” he says. “Multiple approaches will be needed.”

The study was funded by the Down Syndrome Research and Treatment Foundation, Research Down Syndrome, the intramural programs of the National Institute on Alcohol Abuse and Alcoholism, and the national institutes of Child Health and Human Development, Mental Health, and Neurological Disorders and Stroke.

Source: Johns Hopkins University