News & Views
Issue No. 12, 2009
After a period of reorganization, we are pleased to announce that the Center for Research and Treatment of Down Syndrome here at Stanford is starting a new era. Co-directors Dr. Craig Garner, Dr. Heidi Feldman, and Dr. Craig Heller are transforming the Center into a place where the discovery of therapeutic strategies for the improvement of cognition in Down syndrome is top priority. Read more about our mission in the message from the directors.
In line with our new leadership goals, we would like to inform you about some exciting research conducted at Stanford by Dr. Ahmad Salehi (pictured) and his collaborators. This research has revealed another potential therapeutic strategy to improve learning in a mouse model of Down syndrome. However, we would like to emphasize that these studies were done in a mouse model and more work is required before commencing clinical trials in humans. Read more in the News & Views article below or check out the Stanford School of Medicine press release.
Stanford Researchers Find Another Potential Therapeutic Strategy to Improve Cognition in Down Syndrome
By Sietske N. Heyn, PhD with contribution from Daniel Z. Wetmore, PhD
Dr. Ahmad Salehi and his colleagues recently published exciting findings based on research conducted at the Stanford University School of Medicine. These findings reveal potentially new therapeutic strategies for improving cognition in people with Down syndrome.
For the past ten years, Dr. Salehi, MD, PhD, has focused his research on understanding what causes cognitive deficits in people with Down syndrome. The long-term goal of his research is to discover insights that can be used for therapeutic intervention. To accomplish this goal, he has studied a mouse model of Down syndrome with three copies of many of the same genes triplicated in humans with Down syndrome. Like humans with Down syndrome, these mice have deficits in behaviors that require memory or attention and abnormalities in brain regions responsible for these behaviors such as the hippocampus and locus coeruleus.
In their recent publication, Dr. Salehi and colleagues studied a molecule called norepinephrine (or noradrenaline in the UK) and its role in cognitive function. In the brain, cells in the locus coeruleus (LC) use norepinephrine to communicate with other neurons and affect or modify their activity. Brain areas that receive input from the LC include the hippocampus, a region important for learning and memory, as well as areas involved in stress responses, attention, and sleep. However, outside the brain norepinephrine also plays a role in many physiological functions, including blood pressure and heart function.
Dr. Salehi and colleagues found that cells in the LC degenerate in the mouse model of Down syndrome and norepinephrine levels are reduced. They wondered whether a drug therapy designed to enhance LC function and norepinephrine levels could improve behaviors in the mice.
To assess several potential drug therapies, Dr. Salehi and colleagues studied a form of fear conditioning that tests contextual learning, as well as a natural mouse behavior, nestbuilding. First, they confirmed that cells in the hippocampus were still able to respond to norepinephrine despite the degeneration of the LC. Next, they gave the mice either the substance L-DOPS, which gets converted to norepinephrine in the brain, or xamoterol, which mimics norepinephrine and activates its receptors in the hippocampus and elsewhere in the brain. Both types of drugs were able to restore performance in contextual learning and nestbuilding to levels similar to those achieved by normal mice.
Lastly, Dr. Salehi and his co-researchers studied the genetic causes of LC degeneration. To do so, they used mouse models with either two or three copies of the App gene. This gene is thought to play a role in Alzheimer’s disease and is triplicated in Down syndrome. Down syndrome mice with two copies of the App gene but three copies of other genes triplicated in Down syndrome did not have a degenerated LC. However, these mice still made poor nests. These findings suggest that other genes cause impaired nestbuilding in Down syndrome mice. Further research will be necessary to understand which genes these might be and how they affect cognition.
In conclusion, Dr. Salehi and colleagues showed that the LC is degenerated in a mouse model of Down syndrome. Moreover, by supplementing the brain with additional norepinephrine, the neurotransmitter used by the LC to communicate with other cells in the brain, some behaviors were restored close to normal.
These results are promising, but more studies are required before a similar therapy can be tested in people. A key challenge concerns improving cognitive function without undue side effects on other physiological functions of norepinephrine such as wakefulness, arousal, and stress responses. One of the drugs tested by Dr. Salehi and colleagues is L-DOPS, which is converted to norepinephrine in the brain. L-DOPS is approved for use for a blood pressure disorder in Japan with ongoing clinical trials in the US and Europe. However, the doses required to improve cognitive function in mice would likely be unsafe, because they are more than 100 times higher than those used in people. Further research is needed before any such studies can be carried out in clinical trials involving humans.
