Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington's disease.
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.
Dorner
Jenelle L
JL
Program in Neuroscience, Indiana University, Bloomington, IN, USA.
Miller
Benjamin R
BR
Klein
Emma L
EL
Murphy-Nakhnikian
Alexander
A
Andrews
Rachel L
RL
Barton
Scott J
SJ
Rebec
George V
GV
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
D000661:Amphetamine; D001205:Ascorbic Acid