Red Orbit, by April Flowers ~ September 5, 2013

A new compound that dramatically bolsters learning and memory when given on the day of birth to mice with a Down syndrome-like condition has been identified by researchers from Johns Hopkins and the National Institutes of Health (NIH). The findings, published in Science Translational Medicine, shows that the single-dose treatment seems to enable the cerebellum of the rodent’s brains to grow to a normal size.

The compound is a small molecule known as a sonic hedgehog pathway agonist. The research team cautions that it has not been proven safe for human trials in people with Down syndrome. However, they believe their experiments do hold promise for developing drugs like it.

“Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Harper Reeves, PhD, 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.”

Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21, has been the focus of Reeves’ career. Because of this “trisomy,” extra copies of more than 300 genes housed on that chromosome are present in people with Down syndrome. These extra genes lead to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Developing treatments is complicated and difficult since the condition involves so many genes.

The current study used mice that were genetically engineered to have extra copies of approximately half the genes found on human chromosome 21. The mice share many characteristics with people who have Down syndrome. These include relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. The navigational deficiencies of the mice were tested by tracking how readily the animals located a platform while swimming in a so-called water maze.

Previous studies gave the team a baseline for how Down syndrome affects brain development. The current team tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development using a compound – the sonic hedgehog pathway agonist.

The researchers injected the mice with the compound just once, on the day of their 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.

The researchers looked for changes in behavior as well as measuring the cerebellums. “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 treated mice were tested against untreated Down syndrome-like mice as well as normal mice in a variety of ways. They found that the treated mice performed just as well as the normal mice on the water maze test.

Further research is necessary, says Reeves, to understand exactly why the treatment works, because their examination of certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment. One theory is that the treatment strengthened communication between the cerebellum and the hippocampus, which improved learning.

Reeves says the problem with the compound’s potential to become a human drug is that altering an important biological chain of events like the sonic hedgehog could have many unintended consequences throughout the body. Such consequences could include raising the risk of cancer by triggering inappropriate growth. The team intends to investigate more targeted ways to safely harness the power of the sonic hedgehog in the cerebellum.

Reeves cautions that even if his team is successful in developing a clinically useful drug, the drug will not be 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.”