Neural cell adhesion molecule is required for stability of reinnervated neuromuscular junctions
Neural cell adhesion molecule is required for stability of reinnervated neuromuscular junctions
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DOI：
10.1111/j.1460-9568.2009.07049.x
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发表时间：
2010-01-01
影响因子：
3.4
通讯作者：
Rafuse, Victor F.
中科院分区：
文献类型：
--
作者：
Chipman, Peter H.;Franz, Colin K.;Rafuse, Victor F.
研究运动神经元疾病的病因学通常集中在运动神经元死亡作为疾病的病理生理学定义。然而，神经肌肉传递受损和突触退出通常在细胞死亡之前，增加了突触功能异常导致疾病发生的可能性。尽管对维持神经肌肉接头(NMJ)突触完整性的机制知之甚少，但果蝇的研究表明Fasciclin II发挥着重要作用。受这些研究的启发，我们使用突触发生的再神经模型来分析缺乏神经细胞黏附分子(NCAM)的小鼠的神经肌肉功能，Fasciclin II脊椎动物同源物。结果表明，在神经损伤后1个月，野生型和NCAM-/-小鼠的收缩力恢复相同，表明终板得到了适当的改造。这一正常状态只是暂时的，因为NCAM-/-小鼠在损伤后3个月收缩力量和肌纤维数量减少。3个月后，两者都进一步下降。肌纤维退化，不是因为运动神经元死亡，而是因为突触被撤回。尽管NCAM-/-NMJ神经传导最初正常，但3个月后明显受损。有趣的是，选择性地消融运动神经元或肌肉纤维中的NCAM并没有模拟在重新神经NCAM-/-小鼠中观察到的缺陷。综上所述，这些结果表明，在重新支配的NMJ处，NCAM需要维持正常的突触功能，尽管它在突触前或突触后的丢失不足以导致突触失稳。考虑到NCAM在终末雪旺细胞中维持突触完整性的作用，以及NCAM功能障碍如何导致运动神经元功能障碍。
Studies examining the etiology of motoneuron diseases usually focus on motoneuron death as the defining pathophysiology of the disease. However, impaired neuromuscular transmission and synapse withdrawal often precede cell death, raising the possibility that abnormalities in synaptic function contribute to disease onset. Although little is known about the mechanisms maintaining the synaptic integrity of neuromuscular junctions (NMJs), Drosophila studies suggest that Fasciclin II plays an important role. Inspired by these studies we used a reinnervation model of synaptogenesis to analyze neuromuscular function in mice lacking neural cell adhesion molecule (NCAM), the Fasciclin II vertebrate homolog. Our results showed that the recovery of contractile force was the same in wild-type and NCAM-/- mice at 1 month after nerve injury, indicating that endplates were appropriately reformed. This normality was only transient because the contractile force and myofiber number decreased at 3 months after injury in NCAM-/- mice. Both declined further 3 months later. Myofibers degenerated, not because motoneurons died but because synapses were withdrawn. Although neurotransmission was initially normal at reinnervated NCAM-/- NMJs, it was significantly compromised 3 months later. Interestingly, the selective ablation of NCAM from motoneurons, or muscle fibers, did not mimic the deficits observed in reinnervated NCAM-/- mice. Taken together, these results indicate that NCAM is required to maintain normal synaptic function at reinnervated NMJs, although its loss pre-synaptically or post-synaptically is not sufficient to induce synaptic destabilization. Consideration is given to the role of NCAM in terminal Schwann cells for maintaining synaptic integrity and how NCAM dysfunction may contribute to motoneuron disorders.