title: Up-regulation of GLT1 reverses the deficit in cortically evoked striatal ascorbate efflux in the R6/2 mouse model of Huntington's disease.
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 evidence for a link between GLT1 activation and release of AA into the striatal extracellular fluid, and suggest that dysfunction of this system is a key component of HD pathophysiology.
authors.affiliation: Program in Neuroscience and Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Miller
authors.forename: Jenelle L
authors.initials: JL
authors.lastname: Dorner
authors.forename: Kendra D
authors.initials: KD
authors.lastname: Bunner
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gaither
authors.forename: Emma L
authors.initials: EL
authors.lastname: Klein
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Barton
authors.forename: George V
authors.initials: GV
authors.lastname: Rebec
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001206:Ascorbic Acid Deficiency / Q000378:metabolism*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000494:pharmacology; D002443:Ceftriaxone / Q000494:pharmacology; D002540:Cerebral Cortex / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D004558:Electric Stimulation; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis*; D045604:Extracellular Fluid / Q000378:metabolism; D005838:Genotype; D006816:Huntington Disease / Q000378:metabolism*; D007608:Kainic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000502:physiology
chemical_list: D027342:Excitatory Amino Acid Transporter 2; C493396:Slc1a2 protein, mouse; C120673:benzyloxyaspartate; D001224:Aspartic Acid; C020889:dihydrokainic acid; D002443:Ceftriaxone; D001205:Ascorbic Acid; D007608:Kainic Acid