Selective discrimination learning impairments in mice expressing the humanHuntington's disease mutation

Cognitive decline is apparent in the early stages of Huntington's disease a nd progressively worsens throughout the course of the disease. Expression o f the human Huntington's disease mutation in mice (R6/2 line) causes a prog ressive neurological phenotype with motor symptoms resembling those seen in Huntington's disease. Here we describe the cognitive performance of R6/2 m ice 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 o f age, using separate groups of mice for each test. R6/2 mice did not show an overt motor phenotype until similar to 8 weeks of age. However, between 3.5 and 8 weeks of age, R6/2 mice displayed progressive deterioration in sp ecific aspects of learning in the Morris water maze, visual cliff, two-choi ce swim tank, and T-maze tasks. The age of onset and progression of the def icits in the individual tasks differed depending on the particular task dem ands. Thus, as seen in humans with Huntington's disease, R6/2 mice develop progressive learning impairments on cognitive tasks sensitive to frontostri atal and hippocampal function. We suggest that R6/2 mice provide not only a model for studying cognitive and motor changes in trinucleotide repeat dis orders, but also a framework within which the functional efficacy of therap eutic strategies aimed at treating such diseases can be tested.