Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 8, Pages 2414-2427Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5687-08.2009
Keywords
Huntington; striatum; cortex; excitability; glutamate; AMPA receptor; dopamine; dopamine receptor; neurotoxicity; corticostriatal; excitotoxicity
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Funding
- National Institute of Neurological Disorders and Stroke (NINDS) Grant [NS41574]
- High Q Foundation
- Child's Health and Development Institute
- Canadian Institutes of Health Research Grant [MOP 84438]
- Huntington's Disease Society of America
- National Institute of Neurological Disorders and Stroke Grants [NS052536, NS060803]
- National Institute of Child Health and Human Development Grant [HD02274]
- Child Neurology Society
- Vision Research Center at the University of Washington
- Children's Hospital and Regional Medical Center (Seattle, WA)
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Huntington disease is a genetic neurodegenerative disorder that produces motor, neuropsychiatric, and cognitive deficits and is caused by an abnormal expansion of the CAG tract in the huntingtin (htt) gene. In humans, mutated htt induces a preferential loss of medium spiny neurons in the striatum and, to a lesser extent, a loss of cortical neurons as the disease progresses. The mechanisms causing these degenerative changes remain unclear, but they may involve synaptic dysregulation. We examined the activity of the corticostriatal pathway using a combination of electrophysiological and optical imaging approaches in brain slices and acutely dissociated neurons from the YAC128 mouse model of Huntington disease. The results demonstrated biphasic age-dependent changes in corticostriatal function. At 1 month, before the behavioral phenotype develops, synaptic currents and glutamate release were increased. At 7 and 12 months, after the development of the behavioral phenotype, evoked synaptic currents were reduced. Glutamate release was decreased by 7 months and was markedly reduced by 12 months. These age-dependent alterations in corticostriatal activity were paralleled by a decrease in dopamine D-2 receptor modulation of the presynaptic terminal. Together, these findings point to dynamic alterations at the corticostriatal pathway and emphasize that therapies directed toward preventing or alleviating symptoms need to be specifically designed depending on the stage of disease progression.
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