February 26, 2007
A once-a-day, short-term treatment with a drug compound substantially improved learning and memory in mice with Down syndrome symptoms, say researchers at the Stanford University School of Medicine and Lucile Packard Children's Hospital. What's more, the gains lasted for months after the treatment was discontinued.

The researchers are now considering a clinical trial to test whether the compound has a similar effect in humans with Down syndrome.

"This treatment has remarkable potential," said Craig Garner, PhD, professor of psychiatry and behavioral sciences and co-director of Stanford's Down Syndrome Research Center. "So many other drugs have been tried that had no effect all. Our findings clearly open a new avenue for considering how cognitive dysfunction in individuals with Down syndrome might be treated."

There is a catch, though. After some brief, inconclusive studies on cognition enhancement in elderly or mentally impaired people in the 1950s, the FDA withdrew approval for the use the drug -- pentylenetetrazole, or PTZ -- in humans in 1982 because no clear clinical benefit had been established. Until now, that is.

The research, published Feb. 25 in the online edition of Nature Neuroscience, was conducted by Fabian Fernandez, a graduate student in Garner's laboratory.

Fernandez found that affected mice were significantly better able to identify novel objects and navigate a maze -- tasks that simulate difficulties faced by children and adults with Down syndrome -- after being fed 17 daily doses of milk containing a compound called pentylenetetrazole, or PTZ. Treated mice performed as well as their wild-type counterparts for up to two months after drug treatment was discontinued.

"Somehow the drug treatment creates a new capacity for learning," said Garner, who cautions that this new ability may decay over longer periods of time as older, drug-experienced neurons are replaced by younger cells.

The researchers believe that the key to the improvement lies in the fact that PTZ blocks the action of an inhibitory neurotransmitter called GABA. Normal brains maintain a precise ratio between neuronal excitation and inhibition that allows efficient learning. In contrast, it's thought that Down syndrome patients have too much GABA-related inhibition, making it difficult to process information.

"In general, learning involves neuronal excitation in certain parts of the brain," said Garner. "For example, caffeine, which is a stimulant, can make us more attentive and aware, and enhance learning. Conversely, alcohol or sedatives impair our ability to learn."

"My idea was that it might be possible to harness this excitation effect, which at higher doses can be pathological, to benefit people with Down syndrome," said Fernandez.

More than 300,000 people nationwide have Down syndrome, which is caused by an extra copy of chromosome 21. It is the leading cause of mental retardation in the country, and it is also associated with childhood heart disease, leukemia and early onset Alzheimer's disease.