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Human Molecular Genetics Advance Access originally published online on August 11, 2006
Human Molecular Genetics 2006 15(19):2856-2868; doi:10.1093/hmg/ddl224
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease

Damian M. Cummings, Austen J. Milnerwood, Glenn M. Dallérac, Verina Waights, Jacki Y. Brown, Sarat C. Vatsavayai, Mark C. Hirst and Kerry P.S.J. Murphy*

Huntington's Disease Research Forum, Department of Biological Sciences, Open University, Walton Hall, Milton Keynes MK7 6AA, UK

* To whom correspondence should be addressed. Tel: +44 1908652917; Fax: +44 1908654167; Email: k.murphy{at}open.ac.uk

Received June 15, 2006; Accepted August 4, 2006

Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. We report here a progressive derailment of both LTD and short-term plasticity at perirhinal synapses. Layer II/III neurones gradually lose their ability to support LTD, show early nuclear localization of mutant huntingtin and display a progressive loss of membrane integrity (depolarization and loss of cell capacitance) accompanied by a reduction in the expression of D1 and D2 dopamine receptors visualized in layer I of the perirhinal cortex. Importantly, abnormalities in both short-term and long-term plasticity can be reversed by the introduction of a D2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD.


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