The study found that mice with Down syndrome symptoms that received a short term daily treatment of pentylenetetrazole, or PT improved their memory and learning ability.

Better yet, the researchers from the Stanford University School of Medicine and Lucile Packard Children's Hospital found the positive effect lasted for months after the treatment was discontinued.

The researchers are planning to continue their study in clinical trials to test if PTZ has the same or 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, which was created by researchers at Stanford and Packard Children's Hospital in 2003 to develop useful treatment based on current research discoveries for people with Down syndrome.

"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," Garner added.

In the study, Fabian Fernandez, a graduate student in Garner's laboratory, found that after being fed milk containing a low dose of PTZ daily for 17 days, affected mice were much better than ever at identifying novel objects and navigating a maze task that simulated difficulties experienced by patients with Down syndrome.

The mice receiving the PTZ treatment performed just as well as their wild-type counterparts for months even after the treatment was discontinued, according to the researchers.

"Somehow the drug treatment creates a new capacity for learning," said Garner, who cautioned that the effect is not fixed and the newly gained ability may disappear over a period of time as the drug-influenced neurons are replaced by new cells.

The researchers hypothesized that the improvement was achieved because PTZ blocks the action of an inhibitory neurotransmitter called GABA. Normal brains function in a way that it keeps a balance between neuronal excitation and inhibition to allow efficient learning.

By the researchers' account, the Down syndrome patients have too much GABA-related inhibition, which as a result makes it hard for the brains to function normally.

"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."

The study was conducted in a mouse model of Down syndrome in which about 150 genes were triplicated and many cognitive problems the mice suffered also inflict people with Down syndrome.

The researchers tested PTZ in mice with Down syndrome to see how they perform when subject to unfamiliar objects and a T-shape maze.

In the first test, mice were exposed to two similarly sized, yet different objects for 15 minutes. Then 24 hours later, they were exposed to one of the previously seen object and a third new object.   Wild mice spent more time studying the new object while the untreated mice with Down syndrome mice did not show any preference for either object.

In the T shape maze test, mice were first habituated to the long arm of a T-shaped maze and then allowed to explore. Wild-type mice tended to study first one, then the other arm of the maze. In comparison, untreated Down syndrome mice were less methodical.

However, the mice with Down syndrome performed more like the wild-type on both types of tests after a 17-day treatment of PTZ.

Garner and Fernandez discovered that PTZ had to be used for several days until the effect could be detected. But once detected, the effect lasted for up to two months. In a sense, the researchers said the drug's activity profile is similar to that of some well-known psychiatric medications.

"This suggests that it's not just the removal of the excess inhibition that allows learning to occur, but that we're instead strengthening synapses through some type of long-lasting neuronal adaptation," said Garner.

Mice with Down syndrome lacked long term potentiation that needed to be achieved to make the neurons sensitive to excitation, explained Postdoctoral scholar Wade Morishita, PhD, who works in the Stanford laboratory of Professor Rob Malenka, PhD.

Morishita found that chronic treatment of PTZ helped achieve the long term potentiation that made the Drown syndrome mice perform as well as wild-type mice for up to three months after the treatment was discontinued.

Garner and Fernandez said PTZ ’ s history of use in humans could make it easier for researchers to start human trials. But   they strongly cautioned individuals against using PTZ or other similar compounds on their own to treat Down syndrome.

Use of PTZ in humans can only be allowed after trials demonstrate that the drug is effective and safe.  The researchers also cautioned that the drug did not help normal mice with their learning capabilities.

"We ’ re not in the business of cognitive enhancement," said Fernandez. "Basically, we have something that could be one part of the many different medical and environmental interventions that may allow kids with Down syndrome to live more normally."

In addition, PTZ should not be used at high doses though as the study authors cautioned that just as what high doses of caffeine can do to the body, so does PTZ. High doses of PTZ can cause seizure.

In fact, PTZ has been primarily used for the study of epilepsy in animals after some brief, inconclusive studies conducted in elderly or mentally impaired people in the 1950s.

Epilepsy (sometimes referred to as a seizure disorder) is a common chronic neurological condition that is characterized by recurrent unprovoked epileptic seizures, according to wikipedia.com

PTZ has not been approved by the Food and Drug Administration for any treatment since its withdrawal in 1982 when the agency found the drug does not have any clear clinical benefit.

"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.

Dow syndrome, the leading cause of mental retardation, affects more than 300,000 people nationwide in the U.S.   About 5,000 children are born with Down syndrome in the United States each year.  The condition is caused by an extra copy of chromosome 21. Children with this condition have high risk of heart disease, leukemia and early onset Alzheimer’s disease.

For more information about Down syndrome, visit Facts about Down Syndrome.

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