Advances in Down Syndrome Research

(Ivanhoe Newswire) -- Discoveries about the neural basis for memory deficits inherent in Down Syndrome may offer hope of a new strategy for treating the defects with medication.

Children with Down syndrome are not developmentally delayed at birth, but they fall behind as they age. Memory deficits hinder learning and make it difficult for the brain to collect the experiences needed for normal cognitive development.

Now, findings from the Stanford University School of Medicine and Lucile Packard Children's Hospital suggest a new strategy for treating the defects. The study showed that boosting norepinephrine signaling in the brains of mice genetically engineered to mimic Down syndrome improved their cognition.

"If you intervene early enough, you will be able to help kids with Down syndrome to collect and modulate information," Ahmad Salehi, MD, PhD, primary author of the study, was quoted as saying. "Theoretically, that could lead to an improvement in cognitive functions in these kids."

Down syndrome is a genetic disorder caused by an extra copy of chromosome 21. Using a mouse model, Salehi and colleagues examined exactly how the brain malfunctions in Down syndrome. "Cognition doesn't fail in every aspect; it's failing in a structure-dependent fashion," said Salehi.

People with Down syndrome struggle to use spatial and contextual information to form new memories, a function that depends on the hippocampus part of the brain. As a result, they have trouble learning to navigate a new neighborhood or a shopping mall. But they're much better at remembering information linked to colors, sounds or other sensory cues, because such sensory memories are coordinated by a different brain structure, the amygdala.

The researchers sought to determine what could be causing the problems in the hippocampus. Normally, as contextual or relational memories are formed, hippocampal neurons receive norepinephrine from neurons in another part of the brain, the locus coeruleus. Like humans with Down syndrome, the mice in the experiments experienced early degeneration of the locus coeruleus.

When the locus coeruleus broke down, the mice failed at simple cognitive tests that required them to be aware of changes in their surroundings. For instance, the genetically engineered mice, when placed in an unknown cage, did not build nests, in contrast with normal mice, who typically build nests in such circumstances.

By giving norepinephrine precursors to the mice with the Down-syndrome-like condition, the researchers were able to fix the problem. Only a few hours after they received the drugs that converted to norepinephrine in the brain, these mice were just as good at nest-building and related cognitive tests as normal mice. Direct examination of neurons in the hippocampus of the genetically altered mice showed they responded well to norepinephrine.

"We were very surprised to see that, wow, it worked so fast," said Salehi, but added that the drugs' effect also wore off relatively quickly.
 
Enhancement of norepinephrine signaling has been explored for other neurological conditions. Some of the drugs already on the market for depression and attention deficit hyperactivity disorder target the norepinephrine system. Salehi hopes the new results will spur tests of these drugs for Down syndrome.
 
Melanie Manning, MD, director of the Center for Down Syndrome at Lucile Packard Children's Hospital, was quoted as saying, "It's very exciting. We still have a long way to go, but these are very interesting results."

SOURCE: Science Translational Medicine, November 18, 2009

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