News & Views

Issue No. 9, 2007

Scientists in the Garner laboratory at Stanford University have recently published some exciting findings regarding improved cognitive performance in a mouse model of Down syndrome. Using several different drugs, scientists were able to restore cognitive performance in mice to almost normal levels. To their surprise, improved cognitive performance persisted, even after the drug treatment had been terminated.

These research results shed new light on potential mechanisms underlying impaired cognition in Down syndrome and may provide novel strategies for therapeutic possibilities. While this is very encouraging news, it is important to keep in mind that these studies were carried out in animals. The safety and efficacy of the drugs will have to be carefully assessed.

Please be advised that the Down syndrome clinic at the Lucile Packard Children's Hospital is not involved in this research.

In the spotlight

Pharmacotherapy improves cognitive performance in a Down syndrome mouse model
By Sietske Heyn, Ph.D.

One of the hallmarks of Down syndrome is an impairment in cognitive abilities. The severity of cognitive dysfunction varies tremendously between individuals with Down syndrome. However, no matter how small the impairment, it inevitably has a profound impact on the quality of life of the individual with Down syndrome.

Down syndrome is caused by extra genes on a third copy of chromosome 21. How these extra genes alter the structure and function of the brain and how they interfere with cognition remains largely unknown. Research has shown that one area of the brain called the hippocampus is selectively affected in Down syndrome (Aylward et al., 1999, and Pinter et al., 2001).

The hippocampus is an area of the brain that plays an important role in forming, sorting and storing memories. If the structure and function of this brain area is altered, it will greatly affect the acquisition of information (learning) and the long-term storage and retrieval of information (memory). Pennington et al. (2003) for example, showed that hippocampal learning and memory is affected in children with Down syndrome: Children with Down syndrome consistently performed much lower on a pattern recognition memory test than typically developing children matched on mental age.

To better understand the mechanisms underlying changes in the hippocampus of people with Down syndrome, scientists frequently turn to the well-established mouse model Ts65Dn. This mouse model faithfully recapitulates many conditions found in individuals with Down syndrome (For a review see News & Views Issue No. 2). Studies using these mice have shown that the communication between cells in the hippocampus is altered (See for example Belichenko et al., 2004). Normally, hippocampal cells talk to each other using excitatory and inhibitory signals in a carefully balanced manner. In the hippocampus of Ts65Dn mice, communication between cells is imbalanced.

Evidence suggests that this imbalance might be caused by too much inhibitory communication in the hippocampus (Kleschevnikow et al., 2004). According to this hypothesis, too many inhibitory signals between hippocampal cells could lead to suppressed excitatory signaling and an overall reduction in the flow of information. This could interfere with learning and memory, leading to decreased cognitive performance in Ts65Dn mice and perhaps also in people with Down syndrome.

Researchers in the Garner laboratory at Stanford University wanted to pursue this hypothesis and asked the following question: If communication in the hippocampus of Ts65Dn mice is indeed altered due to excess inhibition, could the imbalance in communication between hippocampal cells be reversed, and could this reversal restore cognitive abilities? Fabian Fernandez, a graduate student in the Garner laboratory, designed several simple yet elegant experiments to explore this question.

To evaluate learning and memory in Ts65Dn mice, two rodent learning and memory tasks were selected: 1) a novel object recognition task and 2) a spontaneous alternation task in a maze. In addition to these behavioral tasks, hippocampal brain slices of mice were analyzed using an electrophysiological technique that measures long-term potentiation (LTP), a well-established paradigm for studying the physiological basis of learning and memory. The LTP experiments were carried out by Dr. W. Morishita.

In the novel object recognition task, mice are allowed to explore either two identical or two non-identical objects. The following day, they are exposed to one old object and one new object. The time spent exploring the new object is calculated and used as a measure of memory (See Figure 1).

Figure 1. Novel object recognition task. On day 1, mice are allowed to explore two identical or two different objects. The next day, the mice are allowed to explore one familiar object from the previous day and one novel object. The time that the mice spend with the novel object is recorded.

During the spontaneous alternation task, mice are placed at the bottom of a T-shaped maze and are allowed to explore their surroundings. The spontaneous alternation task takes advantage of a mouse’s tendency to alternate between left and right arm choices during exploration of a T-shaped maze, and is dependent on the animal’s ability to spatially navigate. Performance is measured as the percentage of time the mice alternate between the two arms of the maze (See Figure 2).

Figure 2. During the spontaneous alternation task, a mouse is placed at the bottom of the T-maze. The mouse walks to the intersection and chooses to explore either the right (R) or the left (L) arm of the maze. After exploring one side it will most likely choose to explore the other side, once it reaches the choice point at the intersection again. The percentage of time the mouse alternates between right and left maze sides is calculated.

Young (3-4 month-old) Ts65Dn mice and wild type (WT) controls were tested on both tasks. Ts65Dn mice were significantly impaired in the novel recognition task, as well as in the spontaneous alternation task compared with WT animals. These results suggest that learning and memory is indeed impaired in Ts65Dn mice.

Having established that Ts65Dn mice exhibit cognitive impairments, scientists proceeded to assess whether low doses of picrotoxin (PTX), bilobalide (BB), and pentylenetetrazol (PTZ) could improve novel object recognition performance in Ts65Dn mice. These three drugs were chosen, because they are known to suppress inhibitory signals in the hippocampus. The experimental results were very exciting: all three drugs significantly improved novel object recognition in the Ts65Dn mice, and performance of PTZ-treated animals tested on the spontaneous alternation task also significantly improved. It was even more exciting to observe that two months after treatment with PTZ was terminated, the Ts65Dn mice still showed improved cognitive performance on the novel object recognition task. These long-lasting effects were also confirmed by results from electrophysiological experiments that showed almost normalized LTP in PTZ-treated animals.

What do these results mean?
Recall that communication between hippocampal cells in the Ts65Dn mice is imbalanced and that evidence suggests that this is due to too much inhibitory signaling. The experiments described above were based on the hypothesis that impaired cognition in Down syndrome is caused by too much inhibitory communication between cells in the hippocampus. The drugs PTX, BB, and PTZ were chosen, because they are known to block inhibitory signals in the hippocampus. Since these drugs were able to significantly improve cognitive performance in the Ts65Dn mice, it suggests that too much inhibition may indeed be part of the cause for impaired cognition in Down syndrome. How exactly the drugs work in the hippocampus, however, is not entirely clear. Perhaps by suppressing the extra inhibitory signals, the drugs give the cells in the hippocampus a chance to rewire their communication patterns, such that the balance between excitatory and inhibitory signals is restored. Restoring the balance would, in turn, lead to improved cognition.

What kind of implications might these findings have for people with Down syndrome?
Results from the experiments described in this review revealed that several drugs are able to improve cognitive performance in a mouse model of Down syndrome and that the treatment effect was long-lasting. While these results are very exciting and give us hope that a similar treatment may improve cognition in people with Down syndrome one day, it is too early to implement analogous therapies in humans. It will take time to carefully assess the safety and efficacy of these and potentially other drugs for human use.

References

Aylward, EH, Li, Q, Honeycutt, NA, Warren, AC, Pulsifer, MB, Barta, PE, Chan, MD, Smith, PD, Jerram, M, and Pearlson, GD (1999) MRI volumes of the hippocampus and amygdala in adults with Down's syndrome with and without dementia. Am J Psychiatry.156(4):564-8.
Abstract

Belichenko, PV, Masliah, E, Kleschevnikov, AM, Villar, AJ, Epstein, CJ, Salehi, A, and Mobley, MC (2004) Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. Journal of Comparative Neurology. 480:281-298.
Abstract

Kleschevnikov, AM, Belichenko, PV, Villar, AJ, Epstein, CJ, Malenka, RC, and Mobley, WC (2004) Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci. 24(37):8153-60.
Abstract

Pennington, BF, Moon, J, Edgin, J, Stedron, J, and Nadel, L (2003) The neuropsychology of Down syndrome: Evidence for hippocampal dysfunction. Child Development. 74(1):75-93.
Abstract

Pinter, JD, Brown WE, Eliez, S, Schmitt, JE, Capone, GT, and Reiss, AL (2001) Amygdala and hippocampal volumes in children with Down syndrome: A high-resolution MRI study. Neurology. (56):972-974.
Abstract

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