Reassembly of Excitable Domains after CNS Axon Regeneration
Reassembly of Excitable Domains after CNS Axon Regeneration
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DOI：
10.1523/jneurosci.1747-16.2016
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发表时间：
2016-08-31
影响因子：
5.3
通讯作者：
Rasband, Matthew N.
中科院分区：
文献类型：
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作者：
Marin, Miguel A.;de Lima, Silmara;Rasband, Matthew N.
有髓轴突中动作电位的起始和传播需要离子通道在轴突起始段（AIS）和朗维尔结处聚集。损伤后这些结构域的破坏损害神经系统功能。传统上，受损的CNS轴突被认为是难再生的，但最近的一些方法通过显示强大的长距离再生来挑战这一观点。然而，这些方法是否允许髓鞘再生并促进AIS和朗维尔淋巴结的重建尚不清楚。我们使用小鼠视神经挤压作为中枢神经系统创伤性损伤的模型，对神经挤压后AIS和淋巴结破坏进行了详细分析。我们发现AIS的显着破坏和损失的节点在几天内的挤压，并在损伤后1周的节点完全损失。视网膜神经节细胞（RGC）中肿瘤抑制磷酸酶和张力蛋白同源物（Pten）的基因缺失，加上炎症和cAMP对RGC的刺激，显著增强了再生。通过这种治疗，我们发现了RGCAIS的显著重建，髓鞘再生，甚至在压碎部位的近端，内部和远端区域的节点重新组装。再髓鞘化开始于视网膜附近，向远端发展，并通过电子显微镜证实。虽然轴突生长迅速，髓鞘再生和节点离子通道群集慢得多。最后，从RGCs中基因删除ankrexG以阻断AIS重组并不影响轴突再生，表明轴突再生不需要保留神经元极性。总之，我们的研究结果表明，第一次，再生的中枢神经系统轴突可以髓鞘再生和重新组装新的AIS和节点的兰维尔。
Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGCAIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier.