Dysregulation of Ascorbate Release in the Striatum of Behaving Mice Expressing the Huntington's Disease Gene

Abstract

The extracellular fluid of the striatum contains a high level of ascorbate, an antioxidant vitamin known to play a key role in behavioral activation. We assessed the extracellular dynamics of ascorbate in R6/2 mice engineered to express the gene for Huntington's disease (HD), an autosomal dominant condition characterized by the loss of striatal neurons. Slow-scan voltammetry was used to measure striatal ascorbate during anesthesia and subsequent behavioral recovery. Although both the HD mice and their littermate controls had comparable ascorbate levels during anesthesia, the gradual return of behavioral activation over the next 120 min led to dramatically different ascorbate responses: a progressive increase in controls and a 25-50% decline in HD mice. In contrast, 3,4-dihydroxyphenylacetic acid, a major dopamine metabolite, showed no group differences. Behaviorally, HD mice were less active overall than controls and showed a relatively restricted range of spontaneous movements. Both the ascorbate and behavioral deficits were evident in 6-week-old HD mice and persisted in all subsequent test sessions through 10 weeks of age. Collectively, although these results are consistent with inadequate antioxidant protection in the HD striatum, they indicate that the ascorbate deficit is confined to periods of behavioral activation.

Sex differences in behavior and striatal ascorbate release in the 140 CAG knock-in mouse model of Huntington's disease

“…Although the decrease in striatal AA release upon behavioral activation observed in KI males was less prominent and more variable than that previously described in male R6/2 mice, the deficit in male KI mice, ~20-40% was similar to that of R6/2 mice [26]. This deficit suggests that male HD mice may be more susceptible to oxidative stress in the striatum.…”

“…On the day of recording, both the working electrode and an Ag/AgCl reference electrode were fitted into separate microdrives, which were designed to mate with the head-mounted hubs [26]. After the microdrives were prepared, the mouse was lightly anesthetized with chloropent (0.2ml/100g, i.p.)…”

“…Evaluation of R6/2 neurons in culture revealed changes in glutamate (GLU) receptor function, altered membrane properties, and increased striatal cell death after a single-exposure to oxidative stress [5,25]. Increased susceptibility to oxidative stress may be related to a striatal ascorbate (AA) deficit observed in these mice [26]. In fact, AA treatment and resulting increases in extracellular concentrations of AA in the striatum attenuated the behavioral phenotype [27] and normalized excessive striatal neuronal activity in R6/2 mice [28].…”

The use of the R6 transgenic mouse models of Huntington’s disease in attempts to develop novel therapeutic strategies

“…Extracellular ascorbate is reduced in the striatum of R6/2 mice. 142 When animals were treated with intraperitoneal injections of ascorbate, 4 days per week, from 6 -10 weeks of age, there were significant reductions in stereotypic grooming and an increase in cognitive performance was detected. Unfortunately, the authors did not evaluate whether ascorbate administration had any effects on life span, aggregate formation, and neuropathology of R6/2 mice.…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…Therefore, one can speculate that the primary effect of α-lipoic acid may not necessarily be at the level of the CNS. It has been shown that the levels of the antioxidant ascorbate are reduced in the striatal extracellular fluid of R6/ 2 mice during periods of behavioral activation (Rebec et al, 2002). I.p.…”