Huntington's disease (HD) is an autosomal dominant condition characterized by cognitive impairment and progressive loss of motor control. Despite identification of the underlying genetic defect and its mutant protein, huntingtin, effective treatment remains elusive. Although the ultimate pathology in HD involves the death of neurons primarily in the striatum and selected components of the corticostriatal pathway, the onset and progression of the behavioral phenotype is likely to reflect deficits in how the striatum receives and processes information. This line of research has been enhanced by the recent development of transgenic and knock-in mouse models of HD. In work proposed for this application, we will use these models to build on our long-standing program of research on ascorbate, a water-soluble vitamin critically involved in striatal function. Our overall objective is to assess how a behavior-related deficit in striatal ascorbate release in HD mouse models contributes to motor symptoms. We will test the hypothesis that low ascorbate is linked to alterations in glutamate, an excitatory amino acid released by the corticostriatal pathway. Three parallel approaches are planned. In one, we will use on-line microdialysis to quantify basal extracellular glutamate in behaving HD and wild-type controls. Follow-up experiments will monitor cortically evoked glutamate changes in striatal extracellular fluid and examine mechanisms of extracellular glutamate clearance. Consistent with our prediction, preliminary data indicate that an ascorbate deficit in behaving HD mice indicates elevated striatal glutamate owing to an impaired uptake mechanism. A second approach will examine dysfunctions in striatal neuronal processing by recording single-unit activity in the striatum of HD mouse models during spontaneous movement and sensorimotor stimulation. Follow-up experiments will test hypothesized changes in glutamate receptor sensitivity on abnormally active neurons recorded from awake HD mice and modulation of these changes by ascorbate. A third approach will examine whether reversal of the striatal ascorbate deficit by repeated, intermittent injections of ascorbate leads to a corresponding improvement in the behavioral phenotype. Preliminary data not only support this hypothesis but indicate that ascorbate treatment also reverses abnormalities in striatal neuronal processing. Collectively, these approaches are designed to assess how fluctuations in striatal ascorbate and glutamate contribute to the neuronal malfunctions underlying the motor phenotype of HD. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Sensorimotor Integration Study Section (SMI)
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Sutherland, Margaret L
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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