Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease.

Journal of Neurochemistry
Benjamin R MillerGeorge V Rebec

Abstract

A corticostriatal-dependent deficit in the release of ascorbate (AA), an antioxidant vitamin and neuromodulator, occurs concurrently in striatum with dysfunctional GLT1-dependent uptake of glutamate in the R6/2 mouse model of Huntington's disease (HD), an autosomal dominant condition characterized by overt corticostriatal dysfunction. To determine if deficient striatal AA release into extracellular fluid is related to altered GLT1 activity in HD, symptomatic R6/2 mice between 6 and 9 weeks of age and age-matched wild-type (WT) mice received single daily injections of 200 mg/kg ceftriaxone, a β-lactam antibiotic that elevates the functional expression of GLT1, or saline vehicle for five consecutive days. On the following day, in vivo voltammetry was coupled with corticostriatal afferent stimulation to monitor evoked release of AA into striatum. In saline-treated mice, we found a marked decrease in evoked extracellular AA in striatum of R6/2 relative to WT. Ceftriaxone, in contrast, restored striatal AA in R6/2 mice to WT levels. In addition, intra-striatal infusion of either the GLT1 inhibitor dihydrokainic acid or dl-threo-beta-benzyloxyaspartate blocked evoked striatal AA release. Collectively, our results provide compelling e...Continue Reading

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Citations

Apr 19, 2015·Molecular Neurodegeneration·Mikael MarttinenMikko Hiltunen
Dec 10, 2014·Neurochemical Research·Mikko GyntherDarryl S Pickering
Jul 26, 2016·Frontiers in Human Neuroscience·Kendra D Bunner, George V Rebec
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May 17, 2019·Journal of Neurochemistry·Amy I Smith-DijakLynn A Raymond
Dec 31, 2019·Neuroscience·Bruno José MoraesA Cristina Rego

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