Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination
Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination
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DOI：
10.1093/brain/awg153
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发表时间：
2003-07-01
期刊：
影响因子：
14.5
通讯作者：
Waxman, SG
中科院分区：
文献类型：
--
作者：
Craner, MJ;Lo, AC;Waxman, SG
有髓纤维的特征在于Na（v）1.6钠通道在朗氏结处的轴突膜内聚集，其中它们的存在支持跳跃式传导。在这项研究中，我们使用免疫细胞化学方法研究钠通道的组织沿着轴突在实验性变态反应性脑脊髓炎（EAE），多发性硬化症的模型。我们使用针对钠通道亚型Na（v）1.1、Na（v）1.2、Na（v）1.3和Na（v）1.6产生的亚型特异性抗体研究了视神经内的轴突，视神经是多发性硬化症中常见的CNS通路，以及它们的起源细胞体（视网膜神经节细胞），这些亚型先前已被证明由视网膜神经节细胞表达。我们证明了在EAE中视神经中Na（v）1.6表达到Na（v）1.2表达的显著转变; Na（v）1.6阳性淋巴结的频率降低Na（v）1.2阳性淋巴结的频率增加（对照组为84.5%，EAE组为32.9%）（对照组中11.8% Na（v）1.2免疫阳性淋巴结，EAE组中74.9%）。此外，我们观察到的线性（推测脱髓鞘）轴突配置文件的数量显着增加，证明扩展弥漫性免疫染色Na（v）1.2在EAE与控制视神经。视神经内的这些变化由EAE中视网膜神经节细胞内Na（v）1.6水平降低和Na（v）1.2蛋白水平升高以及Na（v）1.2 mRNA水平升高所证实。我们的Na（v）1.6丢失和Na（v）1.2表达增加的发现表明EAE中的电发生可能恢复到与在未成熟视网膜神经节细胞中观察到的类似的阶段，其中Na（v）1.2通道支持动作电位沿沿着轴突传导。
Myelinated fibres are characterized by the aggregation of Na(v)1.6 sodium channels within the axon membrane at nodes of Ranvier, where their presence supports saltatory conduction. In this study, we used immunocytochemical methods to study the organization of sodium channels along axons in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. We studied axons within the optic nerve, a CNS tract commonly affected in multiple sclerosis, and their cell bodies of origin (retinal ganglion cells), using subtype-specific antibodies generated against sodium channel subtypes Na(v)1.1, Na(v)1.2, Na(v)1.3 and Na(v)1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Na(v)1.6 to Na(v)1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Na(v)1.6-positive nodes (84.5% Na(v)1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Na(v)1.2-positive nodes (11.8% Na(v)1.2 immunopositive nodes in control versus 74.9% in EAE). Moreover, we observed a significant increase in the number of linear (presumably demyelinated) axonal profiles demonstrating extended diffuse immunostaining for Na(v)1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Na(v)1.6 and increased Na(v)1.2 protein, together with increased levels of Na(v)1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Na(v)1.6 and increased expression of Na(v)1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Na(v)1.2 channels support conduction of action potentials along axons.