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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035663-07
Application #
7012787
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Sutherland, Margaret L
Project Start
1996-07-01
Project End
2009-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
7
Fiscal Year
2006
Total Cost
$191,606
Indirect Cost
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
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Rebec, George V (2013) Dysregulation of corticostriatal ascorbate release and glutamate uptake in transgenic models of Huntington's disease. Antioxid Redox Signal 19:2115-28
Estrada-Sánchez, Ana María; Barton, Scott J; Burroughs, Courtney L et al. (2013) Dysregulated striatal neuronal processing and impaired motor behavior in mice lacking huntingtin interacting protein 14 (HIP14). PLoS One 8:e84537
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Miller, Benjamin R; Dorner, Jenelle L; Bunner, Kendra D et al. (2012) Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease. J Neurochem 121:629-38
Murphy-Nakhnikian, Alexander; Dorner, Jenelle L; Fischer, Benjamin I et al. (2012) Abnormal burst patterns of single neurons recorded in the substantia nigra reticulata of behaving 140 CAG Huntington's disease mice. Neurosci Lett 512:1-5
Hong, S Lee; Barton, Scott J; Rebec, George V (2012) Neural correlates of unpredictability in behavioral patterns of wild-type and R6/2 mice. Commun Integr Biol 5:259-61
Estrada-Sánchez, Ana María; Rebec, George V (2012) Corticostriatal dysfunction and glutamate transporter 1 (GLT1) in Huntington's disease: interactions between neurons and astrocytes. Basal Ganglia 2:57-66
Hong, S Lee; Barton, Scott J; Rebec, George V (2012) Altered neural and behavioral dynamics in Huntington's disease: an entropy conservation approach. PLoS One 7:e30879

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