Rheuben Mary B, Autio Dawn M, Xu You-Fen, Atchison William D
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI 48824, USA.
Toxicol Appl Pharmacol. 2004 Apr 15;196(2):266-86. doi: 10.1016/j.taap.2004.01.004.
2,4-Dithiobiuret (DTB) causes ascending motor weakness when given chronically to rodents. In muscles of animals with DTB-induced weakness, quantal release of acetylcholine (ACh) is impaired. We examined in detail the structural changes that occurred at neuromuscular junctions and their associated Schwann cells of extensor digitorum longus (EDL) muscles of male rats treated with DTB to the onset of muscle weakness, 5-8 days. Our objective was to assess the involvement of the Schwann cells and to determine the most likely primary targets of DTB. At the onset of muscle weakness, nerve terminals exhibited some enlarged regions, but did not sprout. Terminal Schwann cells became flatter and expanded to cover most of the endplate. The extent of invasion of the synaptic cleft by Schwann cell processes was not significantly different from controls; extension of Schwann cell sprouts away from the junction was not seen. Thus, the morphology of the Schwann cells, although clearly affected by DTB, does not suggest that they contribute directly to the physiological defects of DTB-treated terminals. Abnormal tubulovesicular structures or tangles of neurofilaments were clustered in the centers of about 25% of treated terminals. Fewer synaptic vesicles occupied the region opposite the postsynaptic folds. Vesicle volumes were variable and included some very large vesicles, corresponding with the variable MEPP amplitudes reported previously for terminals of DTB-treated rodents. The postsynaptic area stained by rhodamine-labeled alpha-bungarotoxin expanded with terminal swelling, apparently by unpleating of the postsynaptic folds. No loss of ACh receptors or spread of ACh receptors beyond terminal boundaries was detected. Morphometric data are consistent with the conclusion that DTB affects, either directly or indirectly, vesicular release of ACh and the subsequent vesicular recycling process.
长期给啮齿动物注射2,4 - 二硫代双缩脲（DTB）会导致上行性运动无力。在DTB诱导的肌无力动物的肌肉中，乙酰胆碱（ACh）的量子释放受损。我们详细研究了用DTB处理至出现肌无力（5 - 8天）的雄性大鼠趾长伸肌（EDL）神经肌肉接头及其相关施万细胞发生的结构变化。我们的目的是评估施万细胞的参与情况，并确定DTB最可能的主要靶点。在肌无力出现时，神经末梢出现一些扩大区域，但未发芽。终末施万细胞变得更扁平并扩展以覆盖大部分终板。施万细胞突起侵入突触间隙的程度与对照组无显著差异；未观察到施万细胞芽从接头处延伸。因此，施万细胞的形态虽然明显受DTB影响，但并不表明它们直接导致了DTB处理的终末的生理缺陷。约25%的处理终末中心聚集有异常的微管泡结构或神经丝缠结。较少的突触小泡占据突触后褶皱相对的区域。小泡体积可变，包括一些非常大的小泡，这与先前报道的DTB处理的啮齿动物终末的微小终板电位（MEPP）幅度变化一致。用罗丹明标记的α - 银环蛇毒素染色的突触后区域随着终末肿胀而扩大，显然是由于突触后褶皱的展开。未检测到ACh受体丢失或ACh受体超出终末边界扩散。形态计量学数据与DTB直接或间接影响ACh的囊泡释放及随后的囊泡再循环过程这一结论一致。
