The role of glutamate uptake on neuronal activity patterns and ascorbate release in striatum of Huntington's disease mice.

摘要

The striatum, which integrates cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by progressive loss of motor control and cognitive decline that worsens until death. Glutamate, a potentially excitotoxic amino acid released by corticostriatal afferents, and ascorbate (vitamin C), an antioxidant vitamin, appear to play crucial roles in HD pathogenesis. For example, the transporter primarily responsible for glutamate uptake (GLT1) is dysfunctional in striatum of mice that model HD, which leads to deficient clearance of synaptic glutamate. Consistent with these findings is that the level of striatal ascorbate release, which is directly linked to the degree of glutamate uptake and corticostriatal excitability, is diminished in HD. Aberrant glutamate and ascorbate handling in striatum, moreover, likely contributes to changes in HD striatal electrophysiology. Interestingly, treatment with ceftriaxone, a beta-lactam antibiotic that up-regulates the functional expression of GLT1, reverses the glutamate uptake deficit and markedly attenuates the HD phenotype in the R6/2 mouse model of HD. Therefore, the overall goal of the this Dissertation was to bring these lines of research together in order to indentify how HD pathology alters striatal neuronal activity patterns and to test the hypothesis that increased glutamate uptake would correct altered activity patterns of striatal neurons and reverse deficient striatal ascorbate release in the R6/2 mice. Using, in vivo electrophysiology in behaving R6/2 mice, I found that striatal neurons have altered activity patterns relative to wild-type (WT) controls. The deficit in R6/2 mice, unfortunately, was not corrected by increasing the level of glutamate uptake with ceftriaxone. In vivo voltammetry, however, revealed that ceftriaxone treatment restored striatal ascorbate release in R6/2 mice to WT levels. Collectively, these results indicate that coordinated firing patterns are a common feature of striatal processing and provide compelling evidence for a direct link between GLT1 activation and striatal ascorbate release. Dysfunction of these mechanisms, moreover, is a cardinal feature of HD pathophysiology. These results also point to ceftriaxone as a potential therapeutic target for HD symptomology.