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The Journal of Neuroscience, April 11, 2007, 27(15):3956-3967; doi:10.1523/JNEUROSCI.4401-06.2007

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Neurobiology of Disease
Anti-GM1 Antibodies Cause Complement-Mediated Disruption of Sodium Channel Clusters in Peripheral Motor Nerve Fibers

Keiichiro Susuki,^1,2 Matthew N. Rasband,² Koujiro Tohyama,³ Katsura Koibuchi,¹ Saori Okamoto,¹ Kei Funakoshi,¹ Koichi Hirata,¹ Hiroko Baba,⁴ and Nobuhiro Yuki¹

¹Department of Neurology and Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan, ²Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, ³The Center for Electron Microscopy and Bio-Imaging Research, Laboratory for Nano-Neuroanatomy, Iwate Medical University, Morioka 020-8505, Japan, and ⁴Department of Molecular Neurobiology, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji 192-0392, Japan

Correspondence should be addressed to either of the following: Keiichiro Susuki, Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3401, Email: ksusuki{at}uchc.edu; or Nobuhiro Yuki, Department of Neurology and Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, Tochigi 321-0293, Japan, Email: yuki{at}dokkyomed.ac.jp

Voltage-gated Na⁺ (Na_v) channels are highly concentrated at nodes of Ranvier in myelinated axons and facilitate rapid action potential conduction. Autoantibodies to gangliosides such as GM1 have been proposed to disrupt nodal Nav channels and lead to Guillain-Barré syndrome, an autoimmune neuropathy characterized by acute limb weakness. To test this hypothesis, we examined the molecular organization of nodes in a disease model caused by immunization with gangliosides. At the acute phase with progressing limb weakness, Na_v channel clusters were disrupted or disappeared at abnormally lengthened nodes concomitant with deposition of IgG and complement products. Paranodal axoglial junctions, the nodal cytoskeleton, and Schwann cell microvilli, all of which stabilize Na_v channel clusters, were also disrupted. The nodal molecules disappeared in lesions with complement deposition but no localization of macrophages. During recovery, complement deposition at nodes decreased, and Na_v channels redistributed on both sides of affected nodes. These results suggest that Na_v channel alterations occur as a consequence of complement-mediated disruption of interactions between axons and Schwann cells. Our findings support the idea that acute motor axonal neuropathy is a disease that specifically disrupts the nodes of Ranvier.

Key words: Guillain-Barré syndrome; node of Ranvier; sodium channel; ganglioside; autoantibodies; complement

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Received July 28, 2006; revised March 4, 2007; accepted March 5, 2007.

Correspondence should be addressed to either of the following: Keiichiro Susuki, Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-3401, Email: ksusuki{at}uchc.edu; or Nobuhiro Yuki, Department of Neurology and Research Institute for Neuroimmunological Diseases, Dokkyo Medical University School of Medicine, Kitakobayashi 880, Mibu, Shimotsuga, Tochigi 321-0293, Japan, Email: yuki{at}dokkyomed.ac.jp

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