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

Cummings, Damian M.; Milnerwood, Austen J.; Dallerac, Glenn M.; Waights, Verina; Brown, Jacki Y.; Vatsavayai, Sarat C.; Hirst, Mark C. and Murphy, Kerry P. S. J. (2006). Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of huntington's disease. Human Molecular Genetics, 15(19) pp. 2856–2868.

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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 D-1 and D-2 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 D-2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD.

Item Type: Journal Article
ISSN: 1460-2083
Keywords: long-term depression; neuronal intranuclear inclusions; striatal spiny neurons; transgenic mice; mutant huntingtin; r6/2 mouse; corticostriatal synapses; degenerative changes; cognitive deficits; perirhinal cortex
Academic Unit/Department: Health and Social Care > Nursing
Health and Social Care
Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 6665
Depositing User: Astrid Peterkin
Date Deposited: 02 Feb 2007
Last Modified: 14 Jan 2016 16:26
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