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  • Review Article
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Nodes of Ranvier during development and repair in the CNS

Nature Reviews Neurology volume 16, pages 426–439 (2020)Cite this article

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Abstract

Saltatory conduction of action potentials along myelinated axons depends on the nodes of Ranvier — small unmyelinated axonal domains where voltage-gated sodium channels are concentrated. Our knowledge of the complex molecular composition of these axonal domains continues to accumulate, although the mechanisms of nodal assembly, which have been elucidated in the PNS, remain only partially understood in the CNS. Besides the key role of the nodes in accelerating conduction, nodal variations are thought to allow the fine tuning of axonal conduction speed to meet information processing needs. In addition, through their multiple glial contacts, nodes seem to be important for neuron–glia interactions. As we highlight in this Review, the disorganization of axonal domains has been implicated in the pathophysiology of various neurological diseases. In multiple sclerosis, for example, nodal and perinodal disruption following demyelination, with subsequent changes in ion channel distribution, leads to altered axonal conduction and integrity. The nodal clusters regenerate concurrently with but also prior to remyelination, allowing the restoration of axonal conduction. In this article, we review current knowledge of the organization and function of nodes of Ranvier in the CNS. We go on to discuss dynamic changes in the nodes during demyelination and remyelination, highlighting the impact of these changes on neuronal physiology in health and disease as well as the associated therapeutic implications.

Key points

  • Nodes of Ranvier allow high-speed saltatory propagation of action potentials along myelinated fibres.

  • A range of mechanisms contribute to nodal protein clustering in the CNS.

  • The presence of multiple glial contacts at the nodal surface suggests that the CNS node might act as an axoglial hub, opening up new perspectives regarding neuroglial communication.

  • Variations in node of Ranvier length and diameter allow the fine-tuning of axonal conduction speed to meet information processing needs at the network scale.

  • Nodal domains might represent sites of axonal vulnerability in demyelinating diseases.

  • The disruption of node of Ranvier and paranodal junctions in CNS demyelinating diseases is associated with voltage-gated sodium and potassium channel redistribution, affecting action potential propagation and axonal integrity.

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Fig. 1: Nodes of Ranvier.
Fig. 2: Neuroglial interactions at the node of Ranvier.
Fig. 3: Molecular composition of the node of Ranvier.
Fig. 4: Determinants of action potential conduction velocity.
Fig. 5: Nodes of Ranvier and myelination and remyelination.

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References

  1. Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nat. Rev. Neurosci. 4, 968–980 (2003).

    CAS  PubMed  Google Scholar 

  2. Faivre-Sarrailh, C. & Devaux, J. J. Neuro-glial interactions at the nodes of Ranvier: implication in health and diseases. Front. Cell. Neurosci. 7, 196 (2013).

    PubMed  PubMed Central  Google Scholar 

  3. Rasband, M. N. & Peles, E. The nodes of Ranvier: molecular assembly and maintenance. Cold Spring Harb. Perspect. Biol. 8, a020495 (2015).

    PubMed  Google Scholar 

  4. Salzer, J. L., Brophy, P. J. & Peles, E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 56, 1532–1540 (2008).

    PubMed  Google Scholar 

  5. Brohawn, S. G. et al. The mechanosensitive ion channel TRAAK is localized to the mammalian node of Ranvier. eLife 8, e50403 (2019).

    PubMed  PubMed Central  Google Scholar 

  6. Kanda, H. et al. TREK-1 and TRAAK are principal K+ channels at the nodes of Ranvier for rapid action potential conduction on mammalian myelinated afferent nerves. Neuron 104, 960–971 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Seidl, A. H. Regulation of conduction time along axons. Neuroscience 276, 126–134 (2014).

    CAS  PubMed  Google Scholar 

  8. Arancibia-Carcamo, I. L. & Attwell, D. The node of Ranvier in CNS pathology. Acta Neuropathol. 128, 161–175 (2014).

    PubMed  PubMed Central  Google Scholar 

  9. Ranvier, L. Contribution à l’histologie et à la physiologie des nerfs périphériques [French]. C. R. Acad. Sci. 73, 1168–1171 (1871).

    Google Scholar 

  10. Ranvier, L-A. Leçons sur l’Histologie du Système Nerveux, par M. L. Ranvier, recueillies par M. Ed. Weber (Librairie F. Savy, 1878).

  11. Lillie, R. S. Factors affecting transmission and recovery in the passive iron nerve model. J. Gen. Physiol. 7, 473–507 (1925).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Peters, A. The formation and structure of myelin sheaths in the central nervous system. J. Biophys. Biochem. Cytol. 8, 431–446 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Uzman, B. G. & Villegas, G. M. A comparison of nodes of Ranvier in sciatic nerves with node-like structures in optic nerves of the mouse. J. Biophys. Biochem. Cytol. 7, 761–762 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Metuzals, J. Ultrastructure of myelinated nerve fibers in the central nervous system of the frog. J. Ultrastruct. Res. 8, 30–47 (1963)

    CAS  PubMed  Google Scholar 

  15. Salzer, J. L. Polarized domains of myelinated axons. Neuron 40, 297–318 (2003).

    CAS  PubMed  Google Scholar 

  16. Arancibia-Carcamo, I. L. et al. Node of Ranvier length as a potential regulator of myelinated axon conduction speed. eLife 6, e23329 (2017).

    PubMed  PubMed Central  Google Scholar 

  17. Micheva, K. D. et al. A large fraction of neocortical myelin ensheathes axons of local inhibitory neurons. eLife 5, e15784 (2016).

    PubMed  PubMed Central  Google Scholar 

  18. Micheva, K. D. et al. Distinctive structural and molecular features of myelinated inhibitory axons in human neocortex. eNeuro 5, ENEURO.0297-18.2018 (2018).

    Google Scholar 

  19. Landon, D. N. & Williams, P. L. Ultrastructure of the node of Ranvier. Nature 199, 575–577 (1963).

    CAS  PubMed  Google Scholar 

  20. Pannese, E. Neurocytology: Fine Structure of Neurons, Nerve Processes, and Neuroglial Cells (Springer International Publishing, 2015).

  21. Ford, M. C. et al. Tuning of Ranvier node and internode properties in myelinated axons to adjust action potential timing. Nat. Commun. 6, 8073–8073 (2015).

    CAS  PubMed  Google Scholar 

  22. Rosenbluth, J. Electrophysiology and morphology of myelinated nerve fibers. V. Intramembranous particle distribution in nerve fiber membranes. Experientia 39, 953–963 (1983).

    CAS  PubMed  Google Scholar 

  23. Edgar, J. M., McCulloch, M. C., Thomson, C. E. & Griffiths, I. R. Distribution of mitochondria along small-diameter myelinated central nervous system axons. J. Neurosci. Res. 86, 2250–2257 (2008).

    CAS  PubMed  Google Scholar 

  24. Ohno, N. et al. Myelination and axonal electrical activity modulate the distribution and motility of mitochondria at CNS nodes of Ranvier. J. Neurosci. 31, 7249–7258 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. D’Este, E. et al. Subcortical cytoskeleton periodicity throughout the nervous system. Sci. Rep. 6, 22741 (2016).

    PubMed  PubMed Central  Google Scholar 

  26. D’Este, E., Kamin, D., Balzarotti, F. & Hell, S. W. Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy. Proc. Natl Acad. Sci. USA 114, E191–E199 (2017).

    PubMed  Google Scholar 

  27. Black, J. A. & Waxman, S. G. The perinodal astrocyte. Glia 1, 169–183 (1988).

    CAS  PubMed  Google Scholar 

  28. Butt, A. M., Duncan, A. & Berry, M. Astrocyte associations with nodes of Ranvier: ultrastructural analysis of HRP-filled astrocytes in the mouse optic nerve. J. Neurocytol. 23, 486–499 (1994).

    CAS  PubMed  Google Scholar 

  29. Butt, A. M. et al. Cells expressing the NG2 antigen contact nodes of Ranvier in adult CNS white matter. Glia 26, 84–91 (1999).

    CAS  PubMed  Google Scholar 

  30. Serwanski, D. R., Jukkola, P. & Nishiyama, A. Heterogeneity of astrocyte and NG2 cell insertion at the node of Ranvier. J. Comp. Neurol. 525, 535–552 (2017).

    CAS  PubMed  Google Scholar 

  31. Ffrench-Constant, C., Miller, R. H., Kruse, J., Schachner, M. & Raff, M. C. Molecular specialization of astrocyte processes at nodes of Ranvier in rat optic nerve. J. Cell Biol. 102, 844–852 (1986).

    CAS  PubMed  Google Scholar 

  32. Dutta, D. J. et al. Regulation of myelin structure and conduction velocity by perinodal astrocytes. Proc. Natl Acad. Sci. USA 115, 11832–11837 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Hildebrand, C. & Waxman, S. G. Postnatal differentiation of rat optic nerve fibers: electron microscopic observations on the development of nodes of Ranvier and axoglial relations. J. Comp. Neurol. 224, 25–37 (1984).

    CAS  PubMed  Google Scholar 

  34. De Biase, L. M., Pucak, M. L., Kang, S. H., Rodriguez, S. N. & Bergles, D. E. Sparse interaction between oligodendrocyte precursor cells (NG2+ cells) and nodes of Ranvier in the central nervous system. bioRxiv https://doi.org/10.1101/185801 (2017).

    Article  Google Scholar 

  35. Zhang, J., Yang, X., Zhou, Y., Fox, H. & Xiong, H. Direct contacts of microglia on myelin sheath and Ranvier’s node in the corpus callosum in rats. J. Biomed. Res. 33, 192–200 (2019).

    PubMed  Google Scholar 

  36. Oohashi, T., Edamatsu, M., Bekku, Y. & Carulli, D. The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity. Exp. Neurol. 274, 134–144 (2015).

    CAS  PubMed  Google Scholar 

  37. Dermietzel, R. Junctions in the central nervous system of the cat. II. A contribution to the tertiary structure of the axonal-glial junctions in the paranodal region of the node of Ranvier. Cell Tissue Res. 148, 577–586 (1974).

    CAS  PubMed  Google Scholar 

  38. Rosenbluth, J., Petzold, C. & Peles, E. Dependence of paranodal junctional gap width on transverse bands. J. Comp. Neurol. 520, 2774–2784 (2012).

    CAS  PubMed  Google Scholar 

  39. Waxman, S. G. & Ritchie, J. M. Molecular dissection of the myelinated axon. Ann. Neurol. 33, 121–136 (1993).

    CAS  PubMed  Google Scholar 

  40. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000).

    CAS  PubMed  Google Scholar 

  41. Patton, D. E., Isom, L. L., Catterall, W. A. & Goldin, A. L. The adult rat brain beta 1 subunit modifies activation and inactivation gating of multiple sodium channel alpha subunits. J. Biol. Chem. 269, 17649–17655 (1994).

    CAS  PubMed  Google Scholar 

  42. Isom, L. L. et al. Structure and function of the beta 2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM motif. Cell 83, 433–442 (1995).

    CAS  PubMed  Google Scholar 

  43. Chen, C. et al. Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β2-subunits. Proc. Natl Acad. Sci. USA 99, 17072 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Namadurai, S. et al. A new look at sodium channel β subunits. Open Biol. 5, 140192 (2015).

    PubMed  PubMed Central  Google Scholar 

  45. Lopez-Santiago, L. F. et al. Sodium channel beta 2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate the response to pain. J. Neurosci. 26, 7984–7994 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Duflocq, A., Le Bras, B., Bullier, E., Couraud, F. & Davenne, M. Nav1.1 is predominantly expressed in nodes of Ranvier and axon initial segments. Mol. Cell. Neurosci. 39, 180–192 (2008).

    CAS  PubMed  Google Scholar 

  47. Van Wart, A. & Matthews, G. Impaired firing and cell-specific compensation in neurons lacking nav1.6 sodium channels. J. Neurosci. 26, 7172–7180 (2006).

    PubMed  PubMed Central  Google Scholar 

  48. Ogiwara, I. et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J. Neurosci. 27, 5903–5914 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lorincz, A. & Nusser, Z. Cell-type-dependent molecular composition of the axon initial segment. J. Neurosci. 28, 14329–14340 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Tian, C., Wang, K., Ke, W., Guo, H. & Shu, Y. Molecular identity of axonal sodium channels in human cortical pyramidal cells. Front. Cell. Neurosci. 8, 297–297 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. Van Wart, A., Trimmer, J. S. & Matthews, G. Polarized distribution of ion channels within microdomains of the axon initial segment. J. Comp. Neurol. 500, 339–352 (2007).

    PubMed  Google Scholar 

  52. Schaller, K. L. & Caldwell, J. H. Expression and distribution of voltage-gated sodium channels in the cerebellum. Cerebellum 2, 2–9 (2003).

    CAS  PubMed  Google Scholar 

  53. Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E. & Levinson, S. R. Sodium channel Na(v)1.6 is localized at nodes of Ranvier, dendrites, and synapses. Proc. Natl Acad. Sci. USA 97, 5616–5620 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Tzoumaka, E. et al. Differential distribution of the tetrodotoxin-sensitive rPN4/NaCh6/Scn8a sodium channel in the nervous system. J. Neurosci. Res. 60, 37–44 (2000).

    CAS  PubMed  Google Scholar 

  55. Schafer, D. P., Custer, A. W., Shrager, P. & Rasband, M. N. Early events in node of Ranvier formation during myelination and remyelination in the PNS. Neuron Glia Biol. 2, 69–79 (2006).

    PubMed  PubMed Central  Google Scholar 

  56. Boiko, T. et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30, 91–104 (2001).

    CAS  PubMed  Google Scholar 

  57. Zhou, W. & Goldin, A. L. Use-dependent potentiation of the Nav1.6 sodium channel. Biophys. J. 87, 3862–3872 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Herzog, R. I., Liu, C., Waxman, S. G. & Cummins, T. R. Calmodulin binds to the C terminus of sodium channels Nav1.4 and Nav1.6 and differentially modulates their functional properties. J. Neurosci. 23, 8261–8270 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Arroyo, E. J. et al. Genetic dysmyelination alters the molecular architecture of the nodal region. J. Neurosci. 22, 1726–1737 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kazen-Gillespie, K. A. et al. Cloning, localization, and functional expression of sodium channel beta1A subunits. J. Biol. Chem. 275, 1079–1088 (2000).

    CAS  PubMed  Google Scholar 

  61. Buffington, S. A. & Rasband, M. N. Na+ channel-dependent recruitment of Navβ4 to axon initial segments and nodes of Ranvier. J. Neurosci. 33, 6191–6202 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chen, C. et al. Mice lacking sodium channel beta1 subunits display defects in neuronal excitability, sodium channel expression, and nodal architecture. J. Neurosci. 24, 4030–4042 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Ratcliffe, C. F., Westenbroek, R. E., Curtis, R. & Catterall, W. A. Sodium channel beta1 and beta3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain. J. Cell Biol. 154, 427–434 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kaplan, M. R. et al. Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of Ranvier. Neuron 30, 105–119 (2001).

    CAS  PubMed  Google Scholar 

  65. Srinivasan, J., Schachner, M. & Catterall, W. A. Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R. Proc. Natl Acad. Sci. USA 95, 15753 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Patino, G. A. & Isom, L. L. Electrophysiology and beyond: multiple roles of Na+ channel β subunits in development and disease. Neurosci. Lett. 486, 53–59 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Malhotra, J. D. et al. Structural requirements for interaction of sodium channel beta 1 subunits with ankyrin. J. Biol. Chem. 277, 26681–26688 (2002).

    CAS  PubMed  Google Scholar 

  68. Kim, D. Y. et al. BACE1 regulates voltage-gated sodium channels and neuronal activity. Nat. Cell Biol. 9, 755–764 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Devaux, J. J., Kleopa, K. A., Cooper, E. C. & Scherer, S. S. KCNQ2 is a nodal K+ channel. J. Neurosci. 24, 1236–1244 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2613 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Schwarz, J. R. et al. KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J. Physiol. 573, 17–34 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Battefeld, A., Tran, B. T., Gavrilis, J., Cooper, E. C. & Kole, M. H. P. Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons. J. Neurosci. 34, 3719–3732 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Devaux, J. et al. Kv3.1b is a novel component of CNS nodes. J. Neurosci. 23, 4509–4518 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Lien, C.-C. & Jonas, P. Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J. Neurosci. 23, 2058–2068 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Davis, J. Q., Lambert, S. & Bennett, V. Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+/third FNIII domain-) and NrCAM at nodal axon segments. J. Cell Biol. 135, 1355–1367 (1996).

    CAS  PubMed  Google Scholar 

  76. Zhang, A. et al. Neurofascin 140 is an embryonic neuronal neurofascin isoform that promotes the assembly of the node of Ranvier. J. Neurosci. 35, 2246–2254 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Grumet, M., Mauro, V., Burgoon, M. P., Edelman, G. M. & Cunningham, B. A. Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules. J. Cell Biol. 113, 1399–1412 (1991).

    CAS  PubMed  Google Scholar 

  78. Custer, A. W. et al. The role of the ankyrin-binding protein NrCAM in node of Ranvier formation. J. Neurosci. 23, 10032–10039 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Feinberg, K. et al. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier. Neuron 65, 490–502 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rios, J. C. et al. Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J. Neurosci. 20, 8354–8364 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Lustig, M. et al. Nr-CAM and neurofascin interactions regulate ankyrin G and sodium channel clustering at the node of Ranvier. Curr. Biol. 11, 1864–1869 (2001).

    CAS  PubMed  Google Scholar 

  82. Labasque, M. & Faivre-Sarrailh, C. GPI-anchored proteins at the node of Ranvier. FEBS Lett. 584, 1787–1792 (2010).

    CAS  PubMed  Google Scholar 

  83. Leterrier, C., Brachet, A., Dargent, B. & Vacher, H. Determinants of voltage-gated sodium channel clustering in neurons. Semin. Cell Dev. Biol. 22, 171–177 (2011).

    CAS  PubMed  Google Scholar 

  84. Berghs, S. et al. betaIV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system. J. Cell Biol. 151, 985–1002 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Jenkins, S. M. & Bennett, V. Developing nodes of Ranvier are defined by ankyrin-G clustering and are independent of paranodal axoglial adhesion. Proc. Natl Acad. Sci. USA 99, 2303–2308 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Garrido, J. J. et al. A targeting motif involved in sodium channel clustering at the axonal initial segment. Science 300, 2091–2094 (2003).

    CAS  PubMed  Google Scholar 

  87. Gasser, A. et al. An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier. J. Neurosci. 32, 7232–7243 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bekku, Y. & Oohashi, T. Neurocan contributes to the molecular heterogeneity of the perinodal ECM. Arch. Histol. Cytol. 73, 95–102 (2010).

    CAS  PubMed  Google Scholar 

  89. Bekku, Y. et al. Bral1: its role in diffusion barrier formation and conduction velocity in the CNS. J. Neurosci. 30, 3113–3123 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Bekku, Y., Rauch, U., Ninomiya, Y. & Oohashi, T. Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS. J. Neurochem. 108, 1266–1276 (2009).

    CAS  PubMed  Google Scholar 

  91. Dours-Zimmermann, M. T. et al. Versican V2 assembles the extracellular matrix surrounding the nodes of Ranvier in the CNS. J. Neurosci. 29, 7731–7742 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Hedstrom, K. L. et al. Neurofascin assembles a specialized extracellular matrix at the axon initial segment. J. Cell Biol. 178, 875–886 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Susuki, K. et al. Three mechanisms assemble central nervous system nodes of Ranvier. Neuron 78, 469–482 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zimmermann, D. R. & Dours-Zimmermann, M. T. Extracellular matrix of the central nervous system: from neglect to challenge. Histochem. Cell Biol. 130, 635–653 (2008).

    CAS  PubMed  Google Scholar 

  95. Melendez-Vasquez, C. et al. Differential expression of proteoglycans at central and peripheral nodes of Ranvier. Glia 52, 301–308 (2005).

    PubMed  Google Scholar 

  96. Weber, P. et al. Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J. Neurosci. 19, 4245–4262 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Bartsch, U., Bartsch, S., Dörries, U. & Schachner, M. Immunohistological localization of tenascin in the developing and lesioned adult mouse optic nerve. Eur. J. Neurosci. 4, 338–352 (1992).

    PubMed  Google Scholar 

  98. Fawcett, J. W., Oohashi, T. & Pizzorusso, T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat. Rev. Neurosci. 20, 451–465 (2019).

    CAS  PubMed  Google Scholar 

  99. Susuki, K. & Rasband, M. N. Molecular mechanisms of node of Ranvier formation. Curr. Opin. Cell Biol. 20, 616–623 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Charles, P. et al. Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction. Curr. Biol. 12, 217–220 (2002).

    CAS  PubMed  Google Scholar 

  101. Girault, J.-A. & Peles, E. Development of nodes of Ranvier. Curr. Opin. Neurobiol. 12, 476–485 (2002).

    CAS  PubMed  Google Scholar 

  102. Bhat, M. A. et al. Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin. Neuron 30, 369–383 (2001).

    CAS  PubMed  Google Scholar 

  103. Boyle, M. E. et al. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30, 385–397 (2001).

    CAS  PubMed  Google Scholar 

  104. Collinson, J. M., Marshall, D., Gillespie, C. S. & Brophy, P. J. Transient expression of neurofascin by oligodendrocytes at the onset of myelinogenesis: implications for mechanisms of axon-glial interaction. Glia 23, 11–23 (1998).

    CAS  PubMed  Google Scholar 

  105. Einheber, S. et al. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J. Cell Biol. 139, 1495–1506 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Menegoz, M. et al. Paranodin, a glycoprotein of neuronal paranodal membranes. Neuron 19, 319–331 (1997).

    CAS  PubMed  Google Scholar 

  107. Sherman, D. L. et al. Neurofascins are required to establish axonal domains for saltatory conduction. Neuron 48, 737–742 (2005).

    CAS  PubMed  Google Scholar 

  108. Tait, S. et al. An oligodendrocyte cell adhesion molecule at the site of assembly of the paranodal axo-glial junction. J. Cell Biol. 150, 657–666 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ogawa, Y. et al. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton. J. Neurosci. 26, 5230–5239 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Chang, K.-J. et al. Glial ankyrins facilitate paranodal axoglial junction assembly. Nat. Neurosci. 17, 1673–1681 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Rasband, M. N. Clustered K+ channel complexes in axons. Neurosci. Lett. 486, 101–106 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Wang, H., Kunkel, D. D., Martin, T. M., Schwartzkroin, P. A. & Tempel, B. L. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature 365, 75–79 (1993).

    CAS  PubMed  Google Scholar 

  113. Vabnick, I. & Shrager, P. Ion channel redistribution and function during development of the myelinated axon. J. Neurobiol. 37, 80–96 (1998).

    CAS  PubMed  Google Scholar 

  114. Traka, M. et al. Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J. Cell Biol. 162, 1161–1172 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Eshed-Eisenbach, Y. & Peles, E. The clustering of voltage-gated sodium channels in various excitable membranes. Dev. Neurobiol. https://doi.org/10.1002/dneu.22728 (2019).

  116. Ghosh, A., Sherman, D. L. & Brophy, P. J. The axonal cytoskeleton and the assembly of nodes of Ranvier. Neuroscientist 24, 104–110 (2018).

    PubMed  Google Scholar 

  117. Rasband, M. N. et al. Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing CNS. J. Neurosci. 19, 7516–7528 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Eshed-Eisenbach, Y. & Peles, E. The making of a node: a co-production of neurons and glia. Curr. Opin. Neurobiol. 23, 1049–1056 (2013).

    CAS  PubMed  Google Scholar 

  119. Susuki, K., Otani, Y. & Rasband, M. N. Submembranous cytoskeletons stabilize nodes of Ranvier. Exp. Neurol. 283, 446–451 (2016).

    PubMed  Google Scholar 

  120. Horresh, I., Bar, V., Kissil, J. L. & Peles, E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B. J. Neurosci. 30, 2480–2489 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang, C., Susuki, K., Zollinger, D. R., Dupree, J. L. & Rasband, M. N. Membrane domain organization of myelinated axons requires βII spectrin. J. Cell Biol. 203, 437–443 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Brivio, V., Faivre-Sarrailh, C., Peles, E., Sherman, D. L. & Brophy, P. J. Assembly of CNS nodes of Ranvier in myelinated nerves is promoted by the axon cytoskeleton. Curr. Biol. 27, 1068–1073 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Zonta, B. et al. Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system. J. Cell Biol. 181, 1169–1177 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Pillai, A. M. et al. Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains. J. Neurosci. Res. 87, 1773–1793 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Rios, J. C. et al. Paranodal interactions regulate expression of sodium channel subtypes and provide a diffusion barrier for the node of Ranvier. J. Neurosci. 23, 7001–7011 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Kaplan, M. R. et al. Induction of sodium channel clustering by oligodendrocytes. Nature 386, 724–728 (1997).

    CAS  PubMed  Google Scholar 

  127. Freeman, S. A. et al. Acceleration of conduction velocity linked to clustering of nodal components precedes myelination. Proc. Natl Acad. Sci. USA 112, E321–E328 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Dubessy, A.-L. et al. Role of a Contactin multi-molecular complex secreted by oligodendrocytes in nodal protein clustering in the CNS. Glia 67, 2248–2263 (2019).

    PubMed  PubMed Central  Google Scholar 

  129. Thetiot, M. et al. An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system. Glia https://doi.org/10.1002/glia.23812 (2020).

  130. Yang, Y., Ogawa, Y., Hedstrom, K. L. & Rasband, M. N. betaIV spectrin is recruited to axon initial segments and nodes of Ranvier by ankyrinG. J. Cell Biol. 176, 509–519 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Hill, A. S. et al. Ion channel clustering at the axon initial segment and node of Ranvier evolved sequentially in early chordates. PLoS Genet. 4, e1000317 (2008).

    PubMed  PubMed Central  Google Scholar 

  132. Yang, Y., Lacas-Gervais, S., Morest, D. K., Solimena, M. & Rasband, M. N. BetaIV spectrins are essential for membrane stability and the molecular organization of nodes of Ranvier. J. Neurosci. 24, 7230–7240 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Dzhashiashvili, Y. et al. Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J. Cell Biol. 177, 857–870 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Ho, T. S.-Y. et al. A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier. Nat. Neurosci. 17, 1664–1672 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Ratcliffe, C. F. et al. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase beta. Nat. Neurosci. 3, 437–444 (2000).

    CAS  PubMed  Google Scholar 

  136. Xiao, Z. C. et al. Tenascin-R is a functional modulator of sodium channel beta subunits. J. Biol. Chem. 274, 26511–26517 (1999).

    CAS  PubMed  Google Scholar 

  137. Kazarinova-Noyes, K. et al. Contactin associates with Na+ channels and increases their functional expression. J. Neurosci. 21, 7517–7525 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Waxman, S. G. & Foster, R. E. Development of the axon membrane during differentiation of myelinated fibres in spinal nerve roots. Proc. R. Soc. Lond. B Biol. Sci. 209, 441–446 (1980).

    CAS  PubMed  Google Scholar 

  139. Waxman, S. G., Black, J. A. & Foster, R. E. Freeze-fracture heterogeneity of the axolemma of premyelinated fibers in the CNS. Neurology 32, 418–421 (1982).

    CAS  PubMed  Google Scholar 

  140. Bonetto, G. et al. Selective axonal expression of the Kv1 channel complex in pre-myelinated GABAergic hippocampal neurons. Front. Cell. Neurosci. 13, 222 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Çolakoğlu, G., Bergstrom-Tyrberg, U., Berglund, E. O. & Ranscht, B. Contactin-1 regulates myelination and nodal/paranodal domain organization in the central nervous system. Proc. Natl Acad. Sci. USA 111, E394–E403 (2014).

    PubMed  PubMed Central  Google Scholar 

  142. Brümmendorf, T. et al. The axonal recognition molecule F11 is a multifunctional protein: specific domains mediate interactions with Ng-CAM and restrictin. Neuron 10, 711–727 (1993).

    PubMed  Google Scholar 

  143. Peles, E. et al. The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin. Cell 82, 251–260 (1995).

    CAS  PubMed  Google Scholar 

  144. Rathjen, F. G., Wolff, J. M. & Chiquet-Ehrismann, R. Restrictin: a chick neural extracellular matrix protein involved in cell attachment co-purifies with the cell recognition molecule F11. Development 113, 151–164 (1991).

    CAS  PubMed  Google Scholar 

  145. Zacharias, U., Nörenberg, U. & Rathjen, F. G. Functional interactions of the immunoglobulin superfamily member F11 are differentially regulated by the extracellular matrix proteins tenascin-R and tenascin-C. J. Biol. Chem. 274, 24357–24365 (1999).

    CAS  PubMed  Google Scholar 

  146. Black, J. A., Foster, R. E. & Waxman, S. G. Rat optic nerve: freeze-fracture studies during development of myelinated axons. Brain Res. 250, 1–20 (1982).

    CAS  PubMed  Google Scholar 

  147. Jinno, S. et al. Neuronal diversity in GABAergic long-range projections from the hippocampus. J. Neurosci. 27, 8790–8804 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Bonifazi, P. et al. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks. Science 326, 1419–1424 (2009).

    CAS  PubMed  Google Scholar 

  149. Hodgkin, A. L. & Huxley, A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. 117, 500–544 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Huxley, A. F. & Stämpfli, R. Evidence for saltatory conduction in peripheral myelinated nerve fibres. J. Physiol. 108, 315–339 (1949).

    PubMed  PubMed Central  Google Scholar 

  151. Tasaki, I. New measurements of the capacity and the resistance of the myelin sheath and the nodal membrane of the isolated frog nerve fiber. Am. J. Physiol. 181, 639–650 (1955).

    CAS  PubMed  Google Scholar 

  152. Cohen, C. C. H. et al. Saltatory conduction along myelinated axons involves a periaxonal nanocircuit. Cell 180, 311–322.e15 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Rushton, W. A. H. A theory of the effects of fibre size in medullated nerve. J. Physiol. 115, 101–122 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Waxman, S. G. & Bennett, M. V. Relative conduction velocities of small myelinated and non-myelinated fibres in the central nervous system. Nat. New Biol. 238, 217–219 (1972).

    CAS  PubMed  Google Scholar 

  155. Debanne, D., Campanac, E., Bialowas, A., Carlier, E. & Alcaraz, G. Axon physiology. Physiol. Rev. 91, 555–602 (2011).

    CAS  PubMed  Google Scholar 

  156. Freeman, S. A., Desmazières, A., Fricker, D., Lubetzki, C. & Sol-Foulon, N. Mechanisms of sodium channel clustering and its influence on axonal impulse conduction. Cell. Mol. Life Sci. 73, 723–735 (2016).

    CAS  PubMed  Google Scholar 

  157. Snaidero, N. & Simons, M. The logistics of myelin biogenesis in the central nervous system. Glia 65, 1021–1031 (2017).

    PubMed  Google Scholar 

  158. Monje, M. Myelin plasticity and nervous system function. Annu. Rev. Neurosci. 41, 61–76 (2018).

    CAS  PubMed  Google Scholar 

  159. Seidl, A. H., Rubel, E. W. & Harris, D. M. Mechanisms for adjusting interaural time differences to achieve binaural coincidence detection. J. Neurosci. 30, 70–80 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Waxman, S. G., Black, J. A., Kocsis, J. D. & Ritchie, J. M. Low density of sodium channels supports action potential conduction in axons of neonatal rat optic nerve. Proc. Natl Acad. Sci. USA 86, 1406–1410 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Johnston, W. L., Dyer, J. R., Castellucci, V. F. & Dunn, R. J. Clustered voltage-gated Na+ channels in Aplysia axons. J. Neurosci. 16, 1730–1739 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Zeng, S. & Jung, P. Simulation analysis of intermodal sodium channel function. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 78, 061916 (2008).

    PubMed  Google Scholar 

  163. Neishabouri, A. & Faisal, A. A. Saltatory conduction in unmyelinated axons: clustering of Na+ channels on lipid rafts enables micro-saltatory conduction in C-fibers. Front. Neuroanat. 8, 109–109 (2014).

    PubMed  PubMed Central  Google Scholar 

  164. Rama, S., Zbili, M. & Debanne, D. Signal propagation along the axon. Curr. Opin. Neurobiol. 51, 37–44 (2018).

    CAS  PubMed  Google Scholar 

  165. Chiu, S. Y. & Ritchie, J. M. On the physiological role of internodal potassium channels and the security of conduction in myelinated nerve fibres. Proc. R. Soc. Lond. B Biol. Sci. 220, 415–422 (1984).

    CAS  PubMed  Google Scholar 

  166. Vabnick, I. et al. Dynamic potassium channel distributions during axonal development prevent aberrant firing patterns. J. Neurosci. 19, 747–758 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Brohawn, S. G., Su, Z. & MacKinnon, R. Mechanosensitivity is mediated directly by the lipid membrane in TRAAK and TREK1 K+ channels. Proc. Natl Acad. Sci. USA 111, 3614–3619 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Renigunta, V., Schlichthörl, G. & Daut, J. Much more than a leak: structure and function of K2p-channels. Pflug. Arch. 467, 867–894 (2015).

    CAS  Google Scholar 

  169. Holland, L., de Regt, H. W. & Drukarch, B. Thinking about the nerve impulse: the prospects for the development of a comprehensive account of nerve impulse propagation. Front. Cell. Neurosci. 13, 208–208 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Gründemann, J. & Clark, B. A. Calcium-activated potassium channels at nodes of Ranvier secure axonal spike propagation. Cell Rep. 12, 1715–1722 (2015).

    PubMed  PubMed Central  Google Scholar 

  171. Tomassy, G. S. et al. Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex. Science 344, 319–324 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Stedehouder, J. et al. Fast-spiking parvalbumin interneurons are frequently myelinated in the cerebral cortex of mice and humans. Cereb. Cortex 27, 5001–5013 (2017).

    CAS  PubMed  Google Scholar 

  173. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Saab, A. S. et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron 91, 119–132 (2016).

    CAS  PubMed  Google Scholar 

  175. Fünfschilling, U. et al. Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517–521 (2012).

    PubMed  PubMed Central  Google Scholar 

  176. Craner, M. J., Lo, A. C., Black, J. A. & Waxman, S. G. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 126, 1552–1561 (2003).

    PubMed  Google Scholar 

  177. Craner, M. J., Hains, B. C., Lo, A. C., Black, J. A. & Waxman, S. G. Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE. Brain 127, 294–303 (2004).

    PubMed  Google Scholar 

  178. Dupree, J. L. et al. Oligodendrocytes assist in the maintenance of sodium channel clusters independent of the myelin sheath. Neuron Glia Biol. 1, 179–192 (2004).

    PubMed  PubMed Central  Google Scholar 

  179. Pfeiffer, F., Frommer-Kaestle, G. & Fallier-Becker, P. Structural adaption of axons during de- and remyelination in the Cuprizone mouse model. Brain Pathol. 29, 675–692 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Mathis, C., Denisenko-Nehrbass, N., Girault, J. A. & Borrelli, E. Essential role of oligodendrocytes in the formation and maintenance of central nervous system nodal regions. Development 128, 4881–4890 (2001).

    CAS  PubMed  Google Scholar 

  181. Rasband, M. N., Kagawa, T., Park, E. W., Ikenaka, K. & Trimmer, J. S. Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination. J. Neurosci. Res. 73, 465–470 (2003).

    CAS  PubMed  Google Scholar 

  182. Black, J. A. et al. Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. Proc. Natl Acad. Sci. USA 97, 11598–11602 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Roostaei, T. et al. Channelopathy-related SCN10A gene variants predict cerebellar dysfunction in multiple sclerosis. Neurology 86, 410–417 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Jukkola, P. I., Lovett-Racke, A. E., Zamvil, S. S. & Gu, C. K+ channel alterations in the progression of experimental autoimmune encephalomyelitis. Neurobiol. Dis. 47, 280–293 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Howell, O. W. et al. Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J. Neuropathol. Exp. Neurol. 69, 1017–1033 (2010).

    PubMed  Google Scholar 

  186. Bagchi, B. et al. Disruption of myelin leads to ectopic expression of KV1.1 channels with abnormal conductivity of optic nerve axons in a cuprizone-induced model of demyelination. PLoS ONE 9, e87736 (2014).

    PubMed  PubMed Central  Google Scholar 

  187. Hamada, M. S. & Kole, M. H. P. Myelin loss and axonal ion channel adaptations associated with gray matter neuronal hyperexcitability. J. Neurosci. 35, 7272–7286 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Craner, M. J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2 + exchanger. Proc. Natl Acad. Sci. USA 101, 8168–8173 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Coman, I. et al. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. Brain 129, 3186–3195 (2006).

    CAS  PubMed  Google Scholar 

  190. Han, C., Huang, J. & Waxman, S. G. Sodium channel Nav1.8: emerging links to human disease. Neurology 86, 473–483 (2016).

    CAS  PubMed  Google Scholar 

  191. Zoupi, L., Markoullis, K., Kleopa, K. A. & Karagogeos, D. Alterations of juxtaparanodal domains in two rodent models of CNS demyelination. Glia 61, 1236–1249 (2013).

    PubMed  Google Scholar 

  192. Fu, Y. et al. Paranodal myelin retraction in relapsing experimental autoimmune encephalomyelitis visualized by coherent anti-Stokes Raman scattering microscopy. J. Biomed. Opt. 16, 106006 (2011).

    PubMed  PubMed Central  Google Scholar 

  193. Stojic, A., Bojcevski, J., Williams, S. K., Diem, R. & Fairless, R. Early nodal and paranodal disruption in autoimmune optic neuritis. J. Neuropathol. Exp. Neurol. 77, 361–373 (2018).

    CAS  PubMed  Google Scholar 

  194. Crawford, D. K., Mangiardi, M., Xia, X., López-Valdés, H. E. & Tiwari-Woodruff, S. K. Functional recovery of callosal axons following demyelination: a critical window. Neuroscience 164, 1407–1421 (2009).

    CAS  PubMed  Google Scholar 

  195. Wolswijk, G. & Balesar, R. Changes in the expression and localization of the paranodal protein Caspr on axons in chronic multiple sclerosis. Brain 126, 1638–1649 (2003).

    PubMed  Google Scholar 

  196. McDonald, W. I. & Sears, T. A. Focal experimental demyelination in the central nervous system. Brain 93, 575–582 (1970).

    CAS  PubMed  Google Scholar 

  197. Bostock, H. & Sears, T. A. The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J. Physiol. 280, 273–301 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Felts, P. A., Baker, T. A. & Smith, K. J. Conduction in segmentally demyelinated mammalian central axons. J. Neurosci. 17, 7267–7277 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Shrager, P. Axonal coding of action potentials in demyelinated nerve fibers. Brain Res. 619, 278–290 (1993).

    CAS  PubMed  Google Scholar 

  200. Hamada, M. S., Popovic, M. A. & Kole, M. H. P. Loss of saltation and presynaptic action potential failure in demyelinated axons. Front. Cell. Neurosci. 11, 45 (2017).

    PubMed  PubMed Central  Google Scholar 

  201. Alrashdi, B. et al. Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis. J. Neuroinflammation 16, 215 (2019).

    PubMed  PubMed Central  Google Scholar 

  202. Schattling, B. et al. Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis. JCI Insight 1, e89810 (2016).

    PubMed  PubMed Central  Google Scholar 

  203. Kapoor, R. et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol. 9, 681–688 (2010).

    CAS  PubMed  Google Scholar 

  204. Raftopoulos, R. et al. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 259–269 (2016).

    CAS  PubMed  Google Scholar 

  205. Brugarolas, P. et al. Development of a PET radioligand for potassium channels to image CNS demyelination. Sci. Rep. 8, 607 (2018).

    PubMed  PubMed Central  Google Scholar 

  206. Nikic, I. et al. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17, 495–499 (2011).

    CAS  PubMed  Google Scholar 

  207. Witte, M. E. et al. Calcium influx through plasma-membrane nanoruptures drives axon degeneration in a model of multiple sclerosis. Neuron 101, 615–624.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Mathey, E. K. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J. Exp. Med. 204, 2363–2372 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Stich, O. et al. Prevalence of neurofascin-155 antibodies in patients with multiple sclerosis. J. Neurol. Sci. 364, 29–32 (2016).

    CAS  PubMed  Google Scholar 

  210. Devaux, J. J., Odaka, M. & Yuki, N. Nodal proteins are target antigens in Guillain–Barré syndrome. J. Peripher. Nerv. Syst. 17, 62–71 (2012).

    CAS  PubMed  Google Scholar 

  211. Elliott, C. et al. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 135, 1819–1833 (2012).

    PubMed  PubMed Central  Google Scholar 

  212. Kawamura, N. et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 81, 714–722 (2013).

    CAS  PubMed  Google Scholar 

  213. Derfuss, T. et al. Contactin-2/TAG-1-directed autoimmunity is identified in multiple sclerosis patients and mediates gray matter pathology in animals. Proc. Natl Acad. Sci. USA 106, 8302–8307 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Cortese, A. et al. Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: clinical relevance of IgG isotype. Neurol. Neuroimmunol. Neuroinflamm. 7, e639 (2019).

    PubMed  PubMed Central  Google Scholar 

  215. Delmont, E. et al. Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy. Brain 140, 1851–1858 (2017).

    PubMed  Google Scholar 

  216. Vallat, J.-M. et al. Subacute nodopathy with conduction blocks and anti-neurofascin 140/186 antibodies: an ultrastructural study. Brain 141, e56 (2018).

    PubMed  Google Scholar 

  217. Querol, L. et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol. 73, 370–380 (2013).

    CAS  PubMed  Google Scholar 

  218. Cortese, A. et al. Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: clinical relevance of IgG isotype. Neurol. Neuroimmunol. Neuroinflamm. 7, e639 (2020).

    PubMed  Google Scholar 

  219. Mathey, E. K. et al. Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies. J. Neuroimmunol. 309, 41–46 (2017).

    CAS  PubMed  Google Scholar 

  220. Devaux, J. J. et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology 86, 800–807 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Kouton, L. et al. Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins. Clin. Neurophysiol. 131, 921–927 (2020).

    PubMed  Google Scholar 

  222. Ogata, H. et al. Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann. Clin. Transl. Neurol. 2, 960–971 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Cortese, A. et al. Neurofascin-155 as a putative antigen in combined central and peripheral demyelination. Neurol. Neuroimmunol. Neuroinflamm. 3, e238 (2016).

    PubMed  PubMed Central  Google Scholar 

  224. Sasaki, M. et al. Molecular reconstruction of nodes of Ranvier after remyelination by transplanted olfactory ensheathing cells in the demyelinated spinal cord. J. Neurosci. 26, 1803–1812 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Smith, K. J., Bostock, H. & Hall, S. M. Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline. J. Neurol. Sci. 54, 13–31 (1982).

    CAS  PubMed  Google Scholar 

  226. Auer, F., Vagionitis, S. & Czopka, T. Evidence for myelin sheath remodeling in the CNS revealed by in vivo imaging. Curr. Biol. 28, 549–559.e3 (2018).

    CAS  PubMed  Google Scholar 

  227. Reimer, M. M. et al. Rapid disruption of axon-glial integrity in response to mild cerebral hypoperfusion. J. Neurosci. 31, 18185–18194 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Ritter, J. et al. Neonatal hyperoxia exposure disrupts axon-oligodendrocyte integrity in the subcortical white matter. J. Neurosci. 33, 8990–9002 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Marin, M. A. et al. Reassembly of excitable domains after CNS axon regeneration. J. Neurosci. 36, 9148–9160 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Marion, C. M., Radomski, K. L., Cramer, N. P., Galdzicki, Z. & Armstrong, R. C. Experimental traumatic brain injury identifies distinct early and late phase axonal conduction deficits of white matter pathophysiology, and reveals intervening recovery. J. Neurosci. 38, 8723–8736 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Eijkelkamp, N. et al. Neurological perspectives on voltage-gated sodium channels. Brain 135, 2585–2612 (2012).

    PubMed  PubMed Central  Google Scholar 

  232. Cooper, E. C. In Jasper’s Basic Mechanisms of the Epilepsies (eds Noebels, J. L. et al.) Chapter 5 (National Center for Biotechnology Information, 2012).

  233. Bauer, C. K. et al. Mutations in KCNK4 that affect gating cause a recognizable neurodevelopmental syndrome. Am. J. Hum. Genet. 103, 621–630 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Desmazières, A., Sol-Foulon, N. & Lubetzki, C. Changes at the nodal and perinodal axonal domains: a basis for multiple sclerosis pathology? Mult. Schler. J. https://doi.org/10.1177/1352458511434370 (2012).

    Article  Google Scholar 

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Acknowledgements

The authors thank the ARSEP foundation, FRM (Fondation pour la Recherche Médicale), Bouvet-Labruyere Family, INSERM-DHOS, APHP (Assistance Publique des Hôpitaux de Paris), “Investissements d’avenir” ANR and NRJ foundation for their precious support related to basic and clinical research on remyelination. We thank Jean Michel Vallat for the electron micrograph of the node of Ranvier, and Rémi Ronzano, Thomas Roux and Elisa Mazuir for assistance with the figures. The authors thank Bernard Zalc for fruitful discussions and careful reading of the manuscript.

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  1. Sorbonne University, Inserm, CNRS, ICM-Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Catherine Lubetzki, Nathalie Sol-Foulon & Anne Desmazières

  2. Assistance Publique des Hôpitaux de Paris (APHP), Neurology Department, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    Catherine Lubetzki

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Lubetzki, C., Sol-Foulon, N. & Desmazières, A. Nodes of Ranvier during development and repair in the CNS. Nat Rev Neurol 16, 426–439 (2020). https://doi.org/10.1038/s41582-020-0375-x

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