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November 28, 2008

A balancing act

A common mechanism may explain cognitive dysfunction during both aging and Alzheimer’s disease

Figure 1: A mouse sitting on a platform in a Morris water maze during a test of its spatial memory.

Cognitive decline may occur during aging, or due to genetic mutations that predispose individuals to develop Alzheimer’s disease. Now, a team of scientists, led by Akihiko Takashima at the RIKEN Brain Science Institute in Wako, has found support for their hypothesis that a similar molecular abnormality could account for cognitive dysfunction during both Alzheimer’s disease and aging. They report their findings in a recent issue of PLoS ONE1.

The researchers subjected aged mice (19–25 months) and adult mice (9–15 months) harboring genetic mutations associated with Alzheimer’s disease to a test of spatial memory—the Morris water maze. Both groups of mice were trained to find a platform submerged in a pool of water based on visual cues around the pool (Fig. 1). When this training period was complete, the researchers could assess how well the mice remembered the platform location by determining how much time the mouse spends near the platform during a ‘probe trial’. They found that both the aged mice and the mice with the Alzheimer’s disease mutations had spatial memory deficits.

The neurotransmitter GABA (γ-aminobutyric acid) controls inhibitory signaling in the brain, and GABA receptor blockers have previously been shown to improve cognition in aging rats. To see if this was also true in Alzheimer mutant mice, the researchers administered a GABA receptor blocker, and saw restoration of normal spatial memory in the Morris water maze. The treated mice were also better at recognizing a new object placed into their cage, which is a measure of ‘declarative memory’.

The researchers then examined synaptic plasticity in a part of the brain that plays a role in spatial memory—the hippocampus. They found deficits in synaptic plasticity in hippocampal slices from both aging and Alzheimer mutant mice. However, normal synaptic plasticity could be restored by adding a GABA receptor blocker. This suggests that both aging and Alzheimer’s disease mutations may affect memory by increasing GABA-mediated inhibitory signaling in the hippocampus.

These findings show that GABA receptor blockers may be an effective therapeutic strategy to enhance cognitive function during both aging and Alzheimer’s disease. This work also indicates that an imbalance between excitatory and inhibitory signaling in the brain may result in memory dysfunction. Yuji Yoshiike, the study’s first author, says the findings suggest that “even when memory declines because of the accumulation of neurotoxic molecules during aging, memory may be improved by restoring the balance between synaptic excitation and inhibition.”

References

  1. Yoshiike, Y., Kimura, T., Yamashita, S., Furudate, H., Mizoroki, T., Murayama, M. & Takashima, A. GABAA receptor-mediated acceleration of aging-associated memory decline in APP/PS1 mice and its pharmacological treatment by picrotoxin. PLoS ONE 3, e3029 (2008). |  | (Link)