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- Title
Cognitive Deficits in the R6/2 mouse model of Huntington's disease and their Amelioration with Donepezil.
- Authors
Murphy, Carol A.; Paterson, Neil E.; Chen, Angela; Arias, Washington; He, Dansha; Alosio, William; Oakeshott, Steven; Farrar, Andrew; Menalled, Liliana; Ramboz, Sylvie; Brunner, Dani; Howland, David; Park, Larry C.
- Abstract
The progressive neurodegenerative disorder Huntington's disease (HD), which is caused by a polyglutamine repeat expansion within the huntingtin protein, is characterized by movement disorders, cognitive impairment, and psychiatric symptoms. Of particular interest for our work, decreased cholinergic function has been reported in HD patients. The R6/2 (120 CAG repeats) mouse model of HD expresses a human transgene containing exon 1 of the mutant huntingtin gene and replicates many of the symptoms of the disease, including marked impairments in cognition and severe motor deficits; moreover, measures of cholinergic function have also been reported to be reduced in this model. We tested whether chronic treatment with the centrally acting reversible acetylcholinesterase inhibitor, donepezil, could improve the performance of R6/2 mice in a simple visual discrimination task, the two-choice swim tank. Mice were trained to swim towards a light cued platform located on one side of a water-filled tank and were tested on acquisition and reversal learning performance. Wild-type (WT) and R6/2 mice were administered donepezil or vehicle starting at 8 weeks of age and tested starting at 9 weeks of age. In the first dose-finding experiment, vehicle-treated R6/2 mice showed a significant deficit during acquisition and reversal as compared to vehicle-treated WT mice. Donepezil (0.6 mg/kg/day) improved reversal in the R6/2 group. In the second experiment, we confirmed the beneficial effect of donepezil (0.06 mg/kg/day) on reversal, and also found beneficial effects on acquisition. Donepezil had no effect on open-field activity measures or latency to reach the platform during the swim test. We suggest that the donepezil-induced improvements in cognitive function observed in the R6/2 transgenic model of HD may reflect amelioration of deficits in cholinergic function that have been reported previously in this model. Further work is required to confirm the findings of these interesting although preliminary studies.
- Subjects
ANIMAL models in research; HUNTINGTON disease; COGNITION disorders; DONEPEZIL; NEURODEGENERATION; POLYGLUTAMINE; HUNTINGTIN protein; MOVEMENT disorders; ACETYLCHOLINESTERASE inhibitors; THERAPEUTICS
- Publication
International Journal of Comparative Psychology, 2014, Vol 27, Issue 3, p397
- ISSN
0889-3667
- Publication type
Article
- DOI
10.46867/ijcp.2014.27.03.08