Early and Persistent Abnormal Decoding by Glial Cells at the Neuromuscular Junction in an ALS Model
Early and Persistent Abnormal Decoding by Glial Cells at the Neuromuscular Junction in an ALS Model
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DOI：
10.1523/jneurosci.1379-14.2015
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发表时间：
2015-01-14
影响因子：
5.3
通讯作者：
Robitaille, Richard
中科院分区：
文献类型：
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作者：
Arbour, Danielle;Tremblay, Elsa;Robitaille, Richard
肌萎缩性侧索硬化症（ALS）是一种迟发性神经肌肉疾病，其特征是在神经肌肉接头（NMJ）去神经支配之前运动神经元（MN）进行性丧失。尽管NMJ去神经支配在ALS中的重要性，但所涉及的机制仍然未被探索和不明确。神经胶质细胞在疾病中的作用已经被强调，包括轴突雪旺细胞激活，先于运动功能的下降和后肢瘫痪的发作。由于NMJ去神经发生在该过程的早期，并且突触周施旺细胞（PSC），NMJ处的神经胶质细胞，调节NMJ的形态稳定性、完整性和修复，因此可以预测PSC功能甚至在去神经之前就会改变，从而导致NMJ功能障碍。我们使用ALS的缓慢进展模型（SOD1（G37R）小鼠）测试了这种可能性。我们观察到一个正常的NMJ组织在ALS的症状前阶段（120天），但PSC检测的内源性突触活动显示细胞内Ca2+的变化增强与野生型同窝仔。这种不适当的PSC解码能力与神经递质释放水平的增加有关，并依赖于与增强的毒蕈碱受体活化相关的内在胶质细胞特性。PSC毒蕈碱受体功能的改变也持续在发病前阶段的疾病，并成为依赖于随着年龄的MN的脆弱性。总之，这些结果表明PSC特性在疾病过程中以不利于NMJ修复的方式改变。PSC功能的损害可能参与了NMJ功能障碍和ALS的发病机制。
Amyotrophic lateral sclerosis (ALS) is a late-onset neuromuscular disease characterized by progressive loss of motor neurons (MNs) preceded by neuromuscular junction (NMJ) denervation. Despite the importance of NMJ denervation in ALS, the mechanisms involved remain unexplored and ill defined. The contribution of glial cells in the disease has been highlighted, including axonal Schwann cell activation that precedes the decline of motor function and the onset of hindlimb paralysis. Because NMJ denervation occurs early in the process and that perisynaptic Schwann cells (PSCs), glial cells at the NMJ, regulate morphological stability, integrity, and repair of the NMJ, one could predict that PSC functions would be altered even before denervation, contributing to NMJ malfunctions. We tested this possibility using a slowly progressive model of ALS (SOD1(G37R) mice). We observed a normal NMJ organization at a presymptomatic stage of ALS (120 d), but PSC detection of endogenous synaptic activity revealed by intracellular Ca2+ changes was enhanced compared with their wild-type littermates. This inappropriate PSC decoding ability was associated with an increased level of neurotransmitter release and dependent on intrinsic glial properties related to enhanced muscarinic receptor activation. The alteration of PSC muscarinic receptor functions also persists during the preonset stage of the disease and became dependent on MN vulnerability with age. Together, these results suggest that PSC properties are altered in the disease process in a manner that would be detrimental for NMJ repair. The impairments of PSC functions may contribute to NMJ dysfunction and ALS pathogenesis.