Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation

Huntington's disease (HD) is an autosomal dominant progressive and fatal ne urodegenerative brain disorder caused by an expanded CAG/polyglutamine repe at in the coding region of the gene. Presymptomatic Huntington's disease pa tients often exhibit cognitive deficits before the onset of classical sympt oms. To investigate the possibility that changes in synaptic plasticity mig ht underlie cognitive impairment in HD, we examined hippocampal synaptic pl asticity and spatial cognition in a transgenic mouse (R6/2 line) expressing exon 1 of the human Huntington's disease gene containing an expanded CAG r epeat. This mouse exhibits a progressive and fatal neurological phenotype t hat resembles Huntington's disease. We report that R6/2 mice show marked al terations in synaptic plasticity at both CA1 and dentate granule cell synap ses, and impaired spatial cognitive performance in the Morris water maze. T he changes in hippocampal plasticity were age dependent, appearing at CA1 s ynapses several weeks before they were observed in the dentate gyrus. Defic its in synaptic plasticity at CA1 synapses occurred before an overt phenoty pe. This suggests that altered synaptic plasticity contributes to the presy mptomatic changes in cognition reported in human carriers of the Huntington ' disease gene. The temporal and regional changes in synaptic plasticity wi thin the hippocampus mirror the appearance of neuronal intranuclear inclusi ons, suggesting a relationship between polyglutamine aggregation and dysfun ction.