title: Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington's disease.
abstract: A behavior-related deficit in the release of ascorbate (AA), an antioxidant vitamin, occurs in the striatum of R6/2 mice expressing the human mutation for Huntington's disease (HD), a dominantly inherited condition characterized by striatal dysfunction. To determine the role of corticostriatal fibers in AA release, we combined slow-scan voltammetry with electrical stimulation of cortical afferents to measure evoked fluctuations in extracellular AA in wild-type (WT) and R6/2 striatum. Although cortical stimulation evoked a rapid increase in AA release in both groups, the R6/2 response had a significantly shorter duration and smaller magnitude than WT. To determine if corticostriatal dysfunction also underlies the behavior-related AA deficit in R6/2s, we measured striatal AA release in separate groups of mice treated with d-amphetamine (5 mg/kg), a psychomotor stimulant known to release AA from corticostriatal terminals independently of dopamine. Relative to WT, both AA release and behavioral activation were diminished in R6/2 mice. Collectively, our results show that the corticostriatal pathway is directly involved in AA release and that this system is dysfunctional in HD. Moreover, because AA release requires glutamate uptake, a failure of striatal AA release in HD is consistent with an overactive glutamate system and diminished glutamate transport, both of which are thought to be central to HD pathogenesis.
authors.affiliation: Program in Neuroscience, Indiana University, Bloomington, IN, USA.
authors.forename: Jenelle L
authors.initials: JL
authors.lastname: Dorner
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Miller
authors.forename: Emma L
authors.initials: EL
authors.lastname: Klein
authors.forename: Alexander
authors.initials: A
authors.lastname: Murphy-Nakhnikian
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Andrews
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Barton
authors.forename: George V
authors.initials: GV
authors.lastname: Rebec
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004563:Electrochemistry; D006816:Huntington Disease / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019680:Trinucleotide Repeat Expansion
chemical_list: D000661:Amphetamine; D001205:Ascorbic Acid