Johnson Michael A, Villanueva Melissa, Haynes Christy L, Seipel Andrew T, Buhler Leah A, Wightman R Mark
Department of Chemistry The University of North Carolina, Chapel Hill, North Carolina, USA.
J Neurochem. 2007 Dec;103(5):2102-10. doi: 10.1111/j.1471-4159.2007.04908.x. Epub 2007 Sep 14.
In this work, the mechanisms responsible for dopamine (DA) release impairments observed previously in Huntington's disease model R6/2 mice were evaluated. Voltammetrically measured DA release evoked in striatal brain slices from 12-week old R6/2 mice by a single electrical stimulus pulse was only 19% of wild-type (WT) control mice. Iontophoresis experiments suggest that the concentration of released DA is not diluted by a larger striatal extracellular volume arising from brain atrophy, but, rather, that striatal dopaminergic terminals have a decreased capacity for DA release. This decreased capacity was not due to an altered requirement for extracellular Ca(2+), and, as in WT mice, the release in R6/2 mice required functioning vesicular transporters. Catecholamine secretion from individual vesicles was measured during exocytosis from adrenal chromaffin cells harvested from R6/2 and WT mice. While the number of exocytotic events was unchanged, the amounts released per vesicle were significantly diminished in R6/2 mice, indicating that vesicular catecholamines are present in decreased amounts. Treatment of chromaffin cells with 3-nitropropionic acid decreased the vesicular release amount from WT cells by 50%, mimicking the release observed from untreated R6/2 cells. Thus, catecholamine release from tissues isolated from R6/2 mice is diminished because of impaired vesicle loading.
在本研究中，我们评估了先前在亨廷顿舞蹈病模型R6/2小鼠中观察到的多巴胺（DA）释放受损的机制。通过单电刺激脉冲诱发12周龄R6/2小鼠纹状体脑片伏安法测量的DA释放量仅为野生型（WT）对照小鼠的19%。离子电泳实验表明，释放的DA浓度并未因脑萎缩导致的纹状体细胞外体积增大而被稀释，而是纹状体多巴胺能终末释放DA的能力下降。这种能力下降并非由于细胞外Ca(2+)需求改变，并且与WT小鼠一样，R6/2小鼠的DA释放需要功能性囊泡转运体。在从R6/2和WT小鼠采集的肾上腺嗜铬细胞胞吐过程中，测量了单个囊泡的儿茶酚胺分泌。虽然胞吐事件的数量没有变化，但R6/2小鼠每个囊泡释放的量显著减少，表明囊泡儿茶酚胺的含量降低。用3-硝基丙酸处理嗜铬细胞可使WT细胞的囊泡释放量减少50%，模拟未处理的R6/2细胞的释放情况。因此，由于囊泡装载受损，从R6/2小鼠分离的组织中儿茶酚胺释放减少。
