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Human Molecular Genetics Advance Access published online on August 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl224
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received June 15, 2006
Accepted August 4, 2006

Article

Aberrant Cortical Synaptic Plasticity and Dopaminergic Dysfunction in a Mouse Model of Huntington's Disease

Damian M. Cummings 1, Austen J. Milnerwood 1, Glenn M. Dallérac 1, Verina Waights 1, Jacki Y. Brown 1, Sarat C. Vatsavayai 1, Mark C. Hirst 1, and Kerry P.S.J. Murphy 1 *

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

* To whom correspondence should be addressed.
Kerry P.S.J. Murphy, E-mail: k.murphy{at}open.ac.uk


  Abstract

Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory and 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 localisation of mutant huntingtin and display a progressive loss of membrane integrity (depolarisation and loss of cell capacitance) accompanied by a reduction in the expression of D1 and D2 dopamine receptors visualised 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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