Human Molecular Genetics Advance Access originally published online on April 6, 2006
Human Molecular Genetics 2006 15(10):1690-1703; doi:10.1093/hmg/ddl092
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Early development of aberrant synaptic plasticity in a mouse model of Huntington's disease
1Huntington's Disease Research Forum and 2Department of Biological Sciences, The Open University, Milton Keynes, UK and 3Department of Neuroscience, Institute of Psychiatry, King's College London, London, UK
* To whom correspondence should be addressed at: Department of Biological Sciences, The Open University, Milton Keynes MK7 6AA, UK. Tel: +44 1908652917; Fax: +44 1908654167; Email: k.murphy{at}open.ac.uk
Received December 14, 2005; Accepted March 29, 2006
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, psychiatric and cognitive decline. Marked neuronal loss occurs in the cortex and striatum. HD is inherited in an autosomal dominant fashion and caused by a trinucleotide repeat expansion (CAG) in the gene encoding the protein huntingtin. Predictive genetic testing has revealed early cognitive deficits in asymptomatic gene carriers at a time when there is little evidence for cell death, suggesting that impaired cognition results from a cellular or synaptic deficit, such as aberrant synaptic plasticity. Altered hippocampal long-term potentiation has been reported in mouse models of HD; however, the relationship between synaptic dysfunction and phenotype progression has not previously been characterized. We examined the age-dependency of aberrant hippocampal synaptic plasticity in the R6/1 mouse model of HD. Long-term depression (LTD) is a developmentally regulated form of plasticity, which normally declines by early adulthood. Young R6/1 mice follow the same pattern of LTD expression as controls, in that they express LTD in the first weeks of life, and then lose the ability with age. Unlike controls, R6/1 synapses later regain the ability to support LTD. This is associated with nuclear localization of mutant huntingtin, but occurs months prior to the formation of nuclear aggregates. We present the first detailed description of a progressive derailment of a functional neural correlate of cognitive processing in HD.
Present address: Department of Psychiatry and Brain Research Centre, University of British Columbia, Vancouver, Canada.
Present address: Mental Retardation Research Center, University of California at Los Angeles, Los Angeles, CA, USA.
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