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The Journal of Neuroscience, February 25, 2009, 29(8):2414-2427; doi:10.1523/JNEUROSCI.5687-08.2009

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Neurobiology of Disease
Age-Dependent Alterations of Corticostriatal Activity in the YAC128 Mouse Model of Huntington Disease

Prasad R. Joshi,^1 * Nan-Ping Wu,^1 * Véronique M. André,¹ Damian M. Cummings,¹ Carlos Cepeda,¹ John A. Joyce,⁵ Jeffrey B. Carroll,^3,4 Blair R. Leavitt,³ Michael R. Hayden,³ Michael S. Levine,¹ and Nigel S. Bamford^2,5,6,7,8 *

¹Mental Retardation Research Center, The David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, ²Center on Human Development and Disability, University of Washington, Seattle, Washington 98105, ³Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics and ⁴Department of Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4, and Departments of ⁵Neurology, ⁶Pediatrics, ⁷Psychology, and ⁸Neurobiology and Behavior, University of Washington and Seattle Children's Hospital, Seattle, Washington 98105

Correspondence should be addressed to Dr. Nigel S. Bamford, University of Washington, Department of Neurology, Box 356465, RR650, 1955 NE Pacific Street, Seattle, WA 98105. Email: bamford{at}u.washington.edu

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 D₂ 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.

Key words: Huntington; striatum; cortex; excitability; glutamate; AMPA receptor; dopamine; dopamine receptor; neurotoxicity; corticostriatal; excitotoxicity

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Received Nov. 28, 2008; revised Jan. 6, 2009; accepted Jan. 23, 2009.

Correspondence should be addressed to Dr. Nigel S. Bamford, University of Washington, Department of Neurology, Box 356465, RR650, 1955 NE Pacific Street, Seattle, WA 98105. Email: bamford{at}u.washington.edu

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