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

Department of Pharmacology, Cambridge Centre for Brain Repair, University of Cambridge, United Kingdom.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2000; 19(23):10428-37.
Source: PubMed


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 approximately 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.


Available from: Lisa Lione, Feb 11, 2014
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    • "As such, we designed these experiments to assess whether the cognitive deficits present in human HD are modeled in the YAC128 mice and to assess how they relate to motor dysfunction and neuropathology. Cognitive deficits have been demonstrated previously in the R6/2 mouse model of polyglutamine toxicity in which learning deficits were shown to precede motor dysfunction (Carter et al., 1999; Lione et al., 1999). Overall, we show cognitive deficits early in the YAC128 mice that precede motor onset and progress to global cognitive impairment in symptomatic mice. "

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    • "However, the use of DMTP and DNMTP tasks in mouse studies has been comparatively limited (Beracochea and Jaffard, 1995; Estapé and Steckler, 2001) and DMTP and DNMTP protocols have yet to be extensively investigated in HD mice. In HD, reversal learning deficits are a particular feature of both the human disease (Lawrence et al., 1998, 1999) and the HD mouse (Lione et al., 1999). Using the DMTP and DNMTP tasks in sequence and serially allows us to utilise a reversal learning shift in conjunction with a working memory probe in murine models of HD. "

    Journal of Neuroscience Methods 08/2015; DOI:10.1016/j.jneumeth.2015.08.022 · 2.05 Impact Factor
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    • "We focused on assessing the impact on the motor phenotype in the R6/1 adult-onset model of HD. R6/1 HD mice also express a fragment of the mutated exon of the human HD gene but the shorter CAG repeat length and single transgene copy results in adult onset of symptoms rather than the juvenile age of onset in R6/2 mice [14]. We confirmed the hypothesis that super-enrichment was able to slow the onset of a range of behavioural dysfunctions in HD mice compared to home-cage enrichment. "
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    ABSTRACT: Huntington's disease (HD) is caused by a tandem repeat expansion and involves progressive cognitive decline, psychiatric abnormalities and motor deficits. Disease onset and progression in HD mice can be substantially delayed by a housing environment with enhanced sensorimotor and cognitive stimulation. However, the proposed benefits of environmental enrichment (EE) are always taken in the context of 'deprived' standard housing and investigation is warranted into the graded effects of enrichment.
    Journal of Huntington's disease 10/2014; 3(3):299-309. DOI:10.3233/JHD-140118
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