Boosting levels of a neurotransmitter in the brain may reverse some of the cognitive abnormalities that characterize Down syndrome, according to a study, published online today (November 18) in Science Translational Medicine, conducted in a mouse model of the disease.

Child with Down syndrome Image: Wikipedia

"The work is really fascinating," said Roger Reeves, a physiologist at Johns Hopkins Medical Institute who studies Down syndrome and was not involved in the research. "The study shows how to take the data from both human and animal model systems and turn them into potential molecules that can be used for therapy."

Down syndrome, a genetic disorder triggered by a third copy of human chromosome 21, is the most common cause of mental retardation in children and leads to deficits in contextual learning and memory. To study the neurological basis for these deficits, Ahmad Salehi and his colleagues at Stanford University School of Medicine turned to a well-established mouse model of the condition, in which mice are engineered to have an extra, third copy of 104 genes on chromosome 16 that are homologous to genes on human chromosome 21.

Mice with such a trisomy are known to show abnormal responses in behavioral tests for contextual learning. They don't respond to fear conditioning, for example -- suggesting they can't learn to associate a shock with a tone. Also, when provided with material with which to build nests, they use much less of it than normal mice and create shabbier homes, again reflecting their decreased ability to respond to new contexts.

The researchers first examined the brains of the mutant mice, and found a significant neurodegeneration in the locus coeruleus (LC), a brain area which produces and supplies other parts of the brain, including the hippocampus, with the neurotransmitter norepinephrine, essential for learning and memory function. That finding matched with the fact that the LC also degenerates in humans with Down syndrome.

"Contextual learning is an indicator of hippocampal function overall," said Reeves. "Finding a way to improve the function of the hippocampus is exactly where we want to go in Down syndrome research."

Since the locus coeruleus produces norepinephrine, the researchers then set out to determine how that neurotransmitter comes into play. When they injected the trisomy mice with l-DOPS, a drug that can cross the blood-brain barrier and convert into norepinephrine, the mice significantly improved their performance in tests of both fear conditioning and nest-building, behaving more like the normal animals. When the drug wore off, so too did the mutants' improved nest-building ability.

"The drug [l-DOPS] was able to restore contextual learning in the mouse model," Salehi said. "Treating [Down syndrome] with norepinephrine could be a new strategy to help improve the condition."

"Even in presence of degeneration the authors showed you can still rescue the function in the brain," said Lynn Nadel, a psychologist at the University of Arizona who studies Down syndrome and was not involved in this study. "Hopefully, this can lead to some sorts of early life interventions in humans."

The LC degeneration the researchers saw in the trisomy mice doesn't just affect humans with Down syndrome -- it is also seen in individuals with Alzheimer's disease and other types of dementia. Also, as many as 25% or more people with Down syndrome go on to develop Alzheimer's-type dementia -- a prevalence estimated to be three to five times greater than that of the general population. This link may arise via the gene App on chromosome 21, which codes for the amyloid precursor protein. This protein can form the amyloid plaques associated with early onset Alzheimer's. In some cases of Down syndrome but not others, App is present in three copies.

That's also true in the model mice, so to explore the relationship between the two diseases, Salehi and his colleagues compared the structure of the LC in trisomy mice with two versus three copies of App. Those with just two copies, they found, had a greater number of neurons producing norepinephrine.

"These results suggest that it may be possible to restore some cognitive function in Alzheimer's patients as well as Down syndrome sufferers using norepinephrine," said Salehi.

Nadel said that the "trick moving forward is to see how to go from this mouse model to a clinical trial in humans."

Reeves pointed out, however, that even before looking into human clinical trials, future studies will need to explore the optimum drug that can enhance the production of norepinephrine.


Related stories:

Alzheimer's clue found
[29th July 2009]

A disease cell line library
[7th August 2008]

Down syndrome traced to one gene
[6th July 2006]