And these trisomy 16 mice, when given norepinephrine, managed to show a strong, but brief, reprieve from their learning disabilities.

For instance, when normal mice are exposed to a sound and then a shock, they learn to associate the noise with the shock: when they hear it, they show signs of fear. Mice with trisomy 16 usually have no problem making the connection between the noise and the pain. However, trisomic mice have significant problems remembering the context they were shocked in -- say, a specific cage -- unless they get a dose of norepinephrine. In Dr. Salehi's study, after dosing, the mice with trisomy 16 learned to pair the context with the memory of shock almost as well as the healthy controls did.


But how long does the effect last? Dr. Salehi isn't sure, but it seems to degrade within two weeks. In another arm of the study, he and his colleagues took mice that had spent some time in separate cages, and introduced them to a new environment (such as a hamster cage). Generally, when this happens, normal mice will gnaw on material to build nests, but trisomy 16 mice won't. When given norepinephrine, the trisomy 16 mice would engage in normal nest-building behavior, but this effect would wear off in about half a month, Dr. Salehi says.

Delivery breakthrough

But to run the study, Dr. Salehi says his main challenge was just delivering the drug. Norepinephrine does not normally cross the blood-brain barrier, so the doctors had to use a pro-drug which could slip through to actually bear the chemical into the brain.

But the pro-drug carried its own dangers: norepinephrine is part of the body's fight-or-flight response, triggered by stress, and the doctors didn't want it released outside the brain where it could tax the heart and cardiovascular system.

The solution was to introduce the pro-drug with carbidopa, a drug that prevents the conversion of the pro-drug into norepinephrine, but which can't itself cross the blood-brain barrier.

But despite the ingenuity of the solution, many challenges remain. Dr. Salehi believes any management of age-related declines in Down syndrome would have to also act on acetylcholine systems, other neurotransmitters that also help the hippocampus function and code memories.

And even then, the treatment wouldn't help with the other deficits in Down syndrome, such as fine motor and language problems. "We only measure limited aspects of cognition in this study," he says. Still, he believes that throughout the life of a person with Down syndrome, the cumulative effects of not receiving the right contextual information by not having adequate levels of norepinephrine in the brain could lead to general cognitive disorders. "One idea is this could lead to failure in learning and memory," he says.


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