Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington's disease.
Corticostriatal dysfunction underlies diminished striatal ascorbate release in the R6/2 mouse model of Huntington's disease.
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DOI：
10.1016/j.brainres.2009.07.019
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发表时间：
2009-09-22
期刊：
影响因子：
2.9
通讯作者：
Rebec GV
中科院分区：
文献类型：
--
作者：
Dorner JL;Miller BR;Klein EL;Murphy-Nakhnikian A;Andrews RL;Barton SJ;Rebec GV
抗坏血酸（AA）（一种抗氧化维生素）释放的行为相关缺陷发生在表达人类亨廷顿病（HD）突变的R6/2小鼠的纹状体中，亨廷顿病是一种以纹状体功能障碍为特征的显性遗传性疾病。为了确定皮质纹状体纤维在AA释放中的作用，我们结合慢扫描伏安法与电刺激皮质传入神经来测量野生型（WT）和R6/2纹状体细胞外AA的诱发波动。虽然皮质刺激诱发AA释放在两组中的快速增加，R6/2反应有一个显着较短的持续时间和较小的幅度比WT。为了确定皮质纹状体功能障碍是否也是R6/2s中行为相关AA缺陷的基础，我们测量了用d-苯丙胺（5 mg/kg）治疗的小鼠的单独组中的纹状体AA释放，d-苯丙胺是一种已知独立于多巴胺从皮质纹状体末端释放AA的精神兴奋剂。相对于WT，R6/2小鼠的AA释放和行为激活均减少。总的来说，我们的研究结果表明，皮质纹状体通路直接参与AA的释放，这一系统是功能失调的HD。此外，由于AA释放需要谷氨酸摄取，纹状体AA释放在HD中的失败与过度活跃的谷氨酸系统和减少的谷氨酸转运一致，这两者都被认为是HD发病机制的核心。
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.
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DOI：
10.1073/pnas.95.11.6480
发表时间：
1998-05-26
影响因子：
11.1
作者：
Cha, JHJ;Kosinski, CM;Young, AB
通讯作者：
Young, AB
影响因子：
14.5
作者：
Behrens, P. F.;Franz, P.;Landwehrmeyer, G. B.
通讯作者：
Landwehrmeyer, G. B.
影响因子：
4.2
作者：
GRUNEWALD, RA;FILLENZ, M
通讯作者：
FILLENZ, M
影响因子：
2.3
作者：
JOYCE, JN;LEXOW, N;WINOKUR, A
通讯作者：
WINOKUR, A
影响因子：
2.9
作者：
KAMATA, K;WILSON, RL;REBEC, GV
通讯作者：
REBEC, GV