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Boosting Cognition in Down Syndrome

18 November 2009 (All day)
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Boosting the level of a brain chemical reverses learning impairments in a mouse model of Down syndrome, researchers report. The work adds to emerging evidence that cognition-enhancing drugs may one day help humans with Down syndrome lead more independent lives.

Down syndrome is the most common cause of mental retardation, affecting approximately one in 800 babies at birth. People with the disorder have an extra copy of chromosome 21, giving them additional copies of hundreds of genes. This somehow alters brain development and causes mild to severe learning disabilities.

To investigate what goes wrong in the brain of someone who has Down syndrome, researchers led by neurobiologist Ahmad Salehi of Stanford University in Palo Alto, California, turned to a genetically modified strain of mice that has three copies of more than 100 of the genes found on human chromosome 21. These so-called Ts65Dn mice exhibit learning and memory deficiencies and other symptoms of Down syndrome. When Salehi and colleagues examined the brains of Ts65Dn mice under a microscope, they discovered degeneration in a region near the base of the brain called the locus coeruleus. This region contains neurons that extend armlike axons all the way to the hippocampus, a key memory center tucked deep inside the temporal lobes. These neurons release the neurotransmitter norepinephrine, which promotes learning and memory in the hippocampus.

Reasoning that the loss of the locus coeruleus neurons might undermine learning and memory by causing a deficit of norepinephrine in the hippocampus, the researchers gave Ts65Dn mice drugs that boost levels of this neurotransmitter throughout the brain. A few hours after delivering the drugs, the researchers tested how well mice were able to learn and remember an enclosure in which they'd received a mild electric shock. Without the drug, Ts65Dn mice performed miserably on this memory test, but with the drug they were as good as normal mice, the researchers report today in Science Translational Medicine.

Because this type of learning depends on the hippocampus, the findings suggest that's where the norepinephrine boost exerts its beneficial effect, Salehi says. Several drugs that enhance norepinephrine are already approved or are in advanced clinical trials for treating low blood pressure and other disorders in humans, which should make it easier to launch a trial in people with Down syndrome if additional animal studies support that approach, Salehi says.

"It's a very positive development," says Roger Reeves, a geneticist at Johns Hopkins University in Baltimore, Maryland. He notes that other recent rodent studies have suggested that drugs that target the neurotransmitter GABA, among others, may also help improve cognition in Down syndrome. Although some researchers have begun to test such cognitive-enhancing drugs in people with Down syndrome, Reeves says the studies to date have been small and fraught with methodological problems, so he doesn't consider them to be reliable. Even so, he says, "5 years ago I never would have believed we would be looking at this kind of fundamental therapy for Down syndrome."

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