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Impaired long-term potentiation in the prefrontal cortex of Huntington’s disease mouse models: rescue by D1 dopamine receptor activation

Dallérac, G. M.; Vatsavayai, S. V.; Cummings, D. M.; Milnerwood, A. J.; Peddie, C. J.; Evans, K. A.; Walters, S. W.; Rezaie, P.; Hirst, M. C. and Murphy, K. P. S. J. (2011). Impaired long-term potentiation in the prefrontal cortex of Huntington’s disease mouse models: rescue by D1 dopamine receptor activation. Neurodegenerative Diseases, 8(4) pp. 230–239.

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Background: The introduction of gene testing for Huntington’s disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs. Objective: We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD. Methods: We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex. Results: We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D1 dopamine receptor agonist (SKF38393). Conclusion: In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction

Item Type: Journal Item
Copyright Holders: 2011 S. Karger AG
ISSN: 1660-2854
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetOpen University Research Development Fund
Not SetNot SetRoyal Society
Keywords: long-term potentiation; Huntington; CAG triplet repeat; synaptic plasticity; synaptopathies
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 34091
Depositing User: Astrid Peterkin
Date Deposited: 26 Jul 2012 08:47
Last Modified: 09 Dec 2018 02:16
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