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Previous Article | Next Article
The Journal of Neuroscience, December 1, 1999, 19(23):10428-10437
Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation
Lisa A. Lione1, 3, 4, Rebecca J. Carter1, Mark J. Hunt1, Gillian P. Bates5, A. Jennifer Morton1, and Stephen B. Dunnett2, 3 Departments of 1 Pharmacology and 2 Experimental Psychology, and 3 Medical Research Council, Cambridge Centre for Brain Repair, University of Cambridge, United Kingdom, 4 Parke-Davis Neuroscience Research Centre, Cambridge, CB2 2QB United Kingdom, and 5 Division of Medical and Molecular Genetics, Guy's Hospital, London, SE1 9RT United Kingdom
Cognitive decline is apparent in the early stages of Huntington's disease and progressively worsens throughout the course of the disease. Expression of the human Huntington's disease mutation in mice (R6/2 line) causes a progressive neurological phenotype with motor symptoms resembling those seen in Huntington's disease. Here we describe the cognitive performance of R6/2 mice using four different tests (Morris water maze, visual cliff avoidance, two-choice swim tank, and T-maze). Behavioral testing was performed on R6/2 transgenic mice and their wild-type littermates between 3 and 14.5 weeks of age, using separate groups of mice for each test. R6/2 mice did not show an overt motor phenotype until ~8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice displayed progressive deterioration in specific aspects of learning in the Morris water maze, visual cliff, two-choice swim tank, and T-maze tasks. The age of onset and progression of the deficits in the individual tasks differed depending on the particular task demands. Thus, as seen in humans with Huntington's disease, R6/2 mice develop progressive learning impairments on cognitive tasks sensitive to frontostriatal and hippocampal function. We suggest that R6/2 mice provide not only a model for studying cognitive and motor changes in trinucleotide repeat disorders, but also a framework within which the functional efficacy of therapeutic strategies aimed at treating such diseases can be tested.
Key words: transgenic mice; Huntington's disease; cognition; behavior; Morris water maze; T-maze
Copyright © 1999 Society for Neuroscience 0270-6474/99/192310428-10$05.00/0
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