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Previous Article | Next Article
The Journal of Neuroscience, July 1, 2000, 20(13):5115-5123
Abnormal Synaptic Plasticity and Impaired Spatial Cognition in Mice Transgenic for Exon 1 of the Human Huntington's Disease Mutation
Kerry P. S. J. Murphy1, Rebecca J. Carter1, Lisa A. Lione2, 3, Laura Mangiarini5, Amarbirpal Mahal5, Gillian P. Bates5, Stephen B. Dunnett2, 4, and A. Jennifer Morton1 1 Department of Pharmacology, 2 Centre for Brain Repair, 3 Parke-Davis Neuroscience Research, and 4 Department of Experimental Psychology, University of Cambridge, CB2 1QJ, United Kingdom, and 5 Division of Medical and Molecular Genetics, GKT School of Medicine, Guy's Hospital, London SE1 9RT, United Kingdom
Huntington's disease (HD) is an autosomal dominant progressive and fatal neurodegenerative brain disorder caused by an expanded CAG/polyglutamine repeat in the coding region of the gene. Presymptomatic Huntington's disease patients often exhibit cognitive deficits before the onset of classical symptoms. To investigate the possibility that changes in synaptic plasticity might underlie cognitive impairment in HD, we examined hippocampal synaptic plasticity and spatial cognition in a transgenic mouse (R6/2 line) expressing exon 1 of the human Huntington's disease gene containing an expanded CAG repeat. This mouse exhibits a progressive and fatal neurological phenotype that resembles Huntington's disease. We report that R6/2 mice show marked alterations in synaptic plasticity at both CA1 and dentate granule cell synapses, and impaired spatial cognitive performance in the Morris water maze. The changes in hippocampal plasticity were age dependent, appearing at CA1 synapses several weeks before they were observed in the dentate gyrus. Deficits in synaptic plasticity at CA1 synapses occurred before an overt phenotype. This suggests that altered synaptic plasticity contributes to the pre-symptomatic changes in cognition reported in human carriers of the Huntington' disease gene. The temporal and regional changes in synaptic plasticity within the hippocampus mirror the appearance of neuronal intranuclear inclusions, suggesting a relationship between polyglutamine aggregation and dysfunction.
Key words: Huntington's disease; long-term potentiation; long-term depression; hippocampus; cognition; intranuclear inclusions; NMDA receptor
Copyright © 2000 Society for Neuroscience 0270-6474/00/20135115-09$05.00/0
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