Paranodal axoglial junctions are essential for rapid nerve conduction and the organization of axonal domains in myelinated axons. Neurofascin155 (Nfasc155) is a glial cell adhesion molecule that is also required for the assembly of these domains. Previous studies have demonstrated that general ablation of Nfasc155 disorganizes these domains, reduces conduction velocity, and disrupts motor behaviors. Multiple sclerosis (MS), a typical disorder of demyelination in the central nervous system, is reported to have autoantibody to Nfasc. However, the impact of focal loss of Nfasc155, which may occur in MS patients, remains unclear. Here, we examined whether restricted focal loss of Nfasc155 affects the electrophysiological properties of the motor system in vivo. Adeno-associated virus type5 (AAV5) harboring EGFP-2A-Cre was injected into the glial-enriched internal capsule of floxed-Neurofascin (NfascFlox/Flox) mice to focally disrupt paranodal junctions in the cortico-fugal fibers from the motor cortex to the spinal cord. Electromyograms (EMGs) of the triceps brachii muscles in response to electrical stimulation of the motor cortex were successively examined in these awake mice. EMG analysis showed significant delay in the onset and peak latencies after AAV injection compared to control (Nfasc+/+) mice. Moreover, EMG half-widths were increased, and EMG amplitudes were gradually decreased by 13 weeks. Similar EMG changes have been reported in MS patients. These findings provide physiological evidence that motor outputs are obstructed by focal ablation of paranodal junctions in myelinated axons. Our findings may open a new path toward development of a novel biomarker for an early phase of human MS, as Nfasc155 detects microstructural changes in the paranodal junction.

中文翻译：

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内囊中节点旁结构域蛋白 Neurofascin155 的局部缺失会损害皮质诱导的体内肌肉活动


节旁轴胶质连接对于快速神经传导和有髓轴突中轴突域的组织至关重要。 Neurofascin155 (Nfasc155) 是一种神经胶质细胞粘附分子，也是这些结构域组装所必需的。先前的研究表明，Nfasc155 的整体消融会扰乱这些区域，降低传导速度，并扰乱运动行为。多发性硬化症 (MS) 是一种典型的中枢神经系统脱髓鞘疾病，据报道具有 Nfasc 自身抗体。然而，多发性硬化症患者中可能发生的 Nfasc155 局灶性缺失的影响仍不清楚。在这里，我们检查了 Nfasc155 的限制性焦点损失是否影响体内运动系统的电生理特性。将携带 EGFP-2A-Cre 的腺相关病毒 5 型 (AAV5) 注射到 floxed-Neurofascin (NfascFlox/Flox) 小鼠富含胶质的内囊中，以局部破坏从运动皮层到大脑皮层的皮质-离体纤维中的节点旁连接。脊髓。在这些清醒的小鼠中，连续检查了肱三头肌对运动皮层电刺激的反应的肌电图（EMG）。 EMG 分析显示，与对照 (Nfasc+/+) 小鼠相比，注射 AAV 后，发病时间和峰值潜伏期显着延迟。此外，13周时肌电图半宽度增加，肌电图振幅逐渐下降。在多发性硬化症患者中也有类似的肌电图变化的报道。这些发现提供了生理学证据，表明运动输出受到有髓轴突中节旁连接的局灶性消融的阻碍。我们的研究结果可能为人类多发性硬化症早期阶段的新型生物标志物的开发开辟一条新途径，因为 Nfasc155 可以检测节旁连接处的微观结构变化。