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DSRTF-funded Study Suggests a New Potential Therapeutic Approach for Cognitive Disabilities in People with Down Syndrome
November, 2009

Most people do not have trouble finding, for example, a specific store in a shopping mall, especially if they have been there before.  They are able to integrate input from their senses (such as sight, sound, smell, etc.) with navigational cues from the environment to remember and find their way.  This is called contextual learning.  For people with Down syndrome, contextual learning is much more difficult as they are often unable to correctly integrate sensory and navigational information.  Furthermore, it is believed that poor contextual learning and memory is involved in additional cognitive decline as people with Down syndrome age.

In a new study by DSRTF-funded researchers, Drs. Ahmad Salehi, William Mobley, and their colleagues at the Stanford University School of Medicine and at the University of California, San Diego (UCSD) School of Medicine explored the basis of contextual learning in a mouse model of Down syndrome and discovered that:

• Specific brain cells, or neurons, in one region of the brain are damaged and degenerate leading to the disruption of a specific set of neural circuits;
• In contrast, the neurons in another brain region that receive signals from the degenerating neurons remain intact and functional;
• One consequence of this specific neuronal degeneration is impairment in contextual learning and memory; and,
• Specific drug compounds can essentially restore this important aspect of learning and memory in the mouse model suggesting a new potential therapeutic strategy

The results of this new study have been published in the biomedical research journal Science Translational Medicine on November 18, 2009.

Like any form of learning, contextual learning and memory involves communication between different regions of the brain (Figure 1a).  Two brain regions—the hippocampus and the locus coeruleus (LC)—have been shown to degenerate in people with Down syndrome and in mouse models of Down syndrome.  The Stanford and UCSD researchers focused on these two brain regions because the hippocampus processes contextual learning and memory, while the LC influences how the hippocampus integrates sensory and navigational information.

The LC sends signals to the hippocampus through a neurotransmitter called norepinephrine.  Norepinephrine is released from cells in the LC and binds to receptors on cells in the hippocampus like a key in a lock.  Once norepinephrine binds to its specific receptors, it triggers a new signal in the hippocampus, which is believed to facilitate contextual learning (Figure 1a).  Norepinephrine regulates the balance between sensory and navigational information entering the hippocampus.  This delicate balance can be disrupted if too little norepinephrine is available in the hippocampus (Figure 1b).

To obtain a better understanding of the mechanisms underlying contextual learning and memory deficits in people with Down syndrome, Drs. Salehi, Mobley, and their colleagues designed experiments, which involved the use of the well-known Ts65Dn Down syndrome mouse model.  This mouse contains over 130 triplicated mouse genes, which are similar to those found on human chromosome 21.

In order to make a useful comparison between Ts65Dn mice and people with Down syndrome, the researchers first had to establish a method to differentiate between contextual learning and memory and other forms of learning and memory in mice.  They designed two experiments for this purpose.  One experiment used a fear conditioning test and the other tested and recorded how well mice make nests.

In the fear conditioning test, the mice learned to relate different cues (such as an odor or a sound) and its environment with an unpleasant experience.  Normally, a mouse would remember that it was exposed to an unpleasant experience when it is placed in the same environment again or if it smells a particular odor or hears a specific sound.  The researchers found that the Ts65Dn mice did not have any trouble remembering the unpleasant experience, as long as they were given the odor or sound cues.  In contrast to control mice (lacking the triplicated genes), without the cues, the Ts65Dn mice were unable to remember that they had previously been exposed to an unpleasant experience in a specific environment.

In an additional test, mice were observed in nest making behavior.  The mice were given a certain amount of nesting material and their nest making was observed in an unknown environment.  Compared to control mice, the Ts65Dn mice made poor nests and used very little of the nesting material.

Since contextual learning involves the release of norepinephrine in the LC, the researchers next compared the levels of norepinephrine in control mice and Ts65Dn mice.  They found that in Ts65Dn mice, the number of norepinephrine releasing cells in the LC was significantly reduced, their size was smaller, and the amount of norepinephrine was decreased, i.e., these cells had undergone degeneration.  At the same time, the number of receptors on the cells in the hippocampus was increased as if to compensate for the reduced amount of norepinephrine signal (Figure 1b).

To test whether increasing norepinephrine levels in the LC could restore contextual learning and memory in the Ts65Dn mice, Drs. Salehi, Mobley and their colleagues administered a pro-drug called L-DOPS (together with another drug to suppress the effects of L-DOPS outside the brain) to these mice.  As a pro-drug, L-DOPS is converted to norepinephrine once it enters the brain (Figure 1c).  The mice were again evaluated during the fear conditioning and nest building tasks.  With L-DOPS administration, the Ts65Dn mice performed almost as well as the control mice in these very specific learning and memory test protocols. 

In addition, the researchers conducted experiments to identify the specific receptors that mediated the beneficial effects of L-DOPS.  For this purpose, mice were treated with another drug called xamoterol, which mimics norepinephrine by binding to a specific subset of norpepinephrine receptors, called b1 adrenergic receptors, on the cells in the hippocampus (Figure 1c).  Xamoterol also improved contextual learning in the Ts65Dn mice, confirming that the norepinephrine receptors, and specifically b1 adrenergic receptors, mediated the rescue of contextual learning and memory in the mouse model of Down syndrome.

To further explore the possible genetic causes leading to the dysfunctional LC in the Ts65Dn mice, several other mouse models were also examined.  One of these mouse models has only two copies of the App gene rather than the three copies of the App gene present in the Ts65Dn mice.  This gene is of particular interest because it has been previously demonstrated to be associated with Alzheimer’s disease and, in earlier DSRTF-supported research, with the degeneration of other brain regions in mouse models of Down syndrome (See Salehi et al., Neuron, 2006, http://www.dsrtf.org/dsnews-070606.htm; http://www.dsrtf.org/dsnews-071806.html).  

Mice with only two copies of the App gene did not exhibit a dysfunctional LC, suggesting that three copies of this gene are necessary for LC degeneration.  However, nesting behavior, and, thus, contextual learning and memory was not restored in this mouse model, suggesting that App is probably not the only gene involved in the contextual learning and memory impairment in the mouse model of Down syndrome.  More research will be required to fully understand the genetic basis of LC degeneration and failed cognition in Down syndrome.

In summary, this recently published study by DSRTF-funded researchers, Drs. Salehi, Mobley, and their colleagues at Stanford and UCSD:

• Identified a new mechanism involved in the degeneration of specific neural circuits in a mouse model of Down syndrome that also leads to impairments in contextual learning and memory; and,
• Showed that by administering the norepinephrine pro-drug L-DOPS or the specific norepinephrine mimic xamoterol to the mouse model of Down syndrome the deficit in contextual learning and memory could be significantly reversed.

These new findings, in part, may explain why contextual learning and memory is compromised in individuals with Down syndrome.  In addition, the results of this study suggest a new potential therapeutic strategy that can be pursued with further research for restoring aspects of this cognitive function and treatment of age-related dementia in individuals with Down syndrome.

Written with the significant collaboration of Sietske N. Heyn, PhD