Glutamate excitotoxicity inflicts paranodal myelin splitting and retraction.
Glutamate excitotoxicity inflicts paranodal myelin splitting and retraction.
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谷氨酸兴奋性毒性导致节旁髓磷脂分裂和回缩。
DOI：
10.1371/journal.pone.0006705
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发表时间：
2009-08-20
期刊：
影响因子：
3.7
通讯作者：
Cheng, Ji-Xin
中科院分区：
文献类型：
--
作者：
Fu, Yan;Sun, Wenjing;Shi, Yunzhou;Shi, Riyi;Cheng, Ji-Xin
在白色物质损伤中观察到结旁髓鞘损伤。然而，造成这种损害的罪魁祸首仍然未知。通过亚微米分辨率的新鲜组织中髓鞘的相干反斯托克斯拉曼散射成像，我们观察到在离体和体内应用谷氨酸后显著的结旁髓鞘分裂和回缩。多模式多光子成像进一步表明，谷氨酸的应用打破了轴神经胶质细胞连接和暴露的aparanodal K+通道，导致轴突传导缺陷，证明了复合动作电位测量。使用4-氨基吡啶，一种广谱的K+通道阻滞剂，有效地恢复了复合动作电位的幅度和宽度。使用汽车成像作为结节长度与直径比的定量读数，观察到应用Ca 2+离子载体A23187的相同类型的结旁髓鞘收缩。此外，从培养基中排除Ca 2+或应用钙蛋白酶抑制剂废除了谷氨酸暴露期间的结旁髓鞘收缩。谷氨酸受体激动剂和拮抗剂的检测进一步表明，结旁髓鞘损伤是由NMDA和红藻氨酸受体介导的。这些结果表明，在患病的白色物质中谷氨酸水平的增加可以通过受体介导的Ca 2+超载和随后的钙蛋白酶激活来损害结旁髓鞘。
Paranodal myelin damage is observed in white matter injury. However the culprit for such damage remains unknown. By coherent anti-Stokes Raman scattering imaging of myelin sheath in fresh tissues with sub-micron resolution, we observed significant paranodal myelin splitting and retraction following glutamate application both ex vivo and in vivo. Multimodal multiphoton imaging further showed that glutamate application broke axo-glial junctions and exposed juxtaparanodal K+ channels, resulting in axonal conduction deficit that was demonstrated by compound action potential measurements. The use of 4-aminopyridine, a broad-spectrum K+ channel blocker, effectively recovered both the amplitude and width of compound action potentials. Using CARS imaging as a quantitative readout of nodal length to diameter ratio, the same kind of paranodal myelin retraction was observed with applications of Ca2+ ionophore A23187. Moreover, exclusion of Ca2+ from the medium or application of calpain inhibitor abolished paranodal myelin retraction during glutamate exposure. Examinations of glutamate receptor agonists and antagonists further showed that the paranodal myelin damage was mediated by NMDA and kainate receptors. These results suggest that an increased level of glutamate in diseased white matter could impair paranodal myelin through receptor-mediated Ca2+ overloading and subsequent calpain activation.
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