Myelin pp 85-106 | Cite as

Physiology of Myelinated Nerve Conduction and Pathophysiology of Demyelination

  • Hessel FranssenEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1190)


Nerve conduction in myelinated axons is a fascinating subject due to the intricate structure and complex properties of the axon and its relation to the equally complex Schwann cells surrounding it. This chapter first deals with normal functional aspects of voltage-gated ion channels in the axon and Schwann cell membranes as well as their related proteins. Next, the pathophysiological alterations that are induced by experimental studies to mimic and study neuropathic disorders in humans are discussed. Finally, a link is made with human neuropathies associated with antibodies against gangliosides, and the putative mechanisms of axonal degeneration in demyelinating neuropathies are discussed. Although this chapter is relevant to understand symptoms in human neuropathies, the reader is referred to Franssen and Straver (Muscle Nerve 49:4–20, 2014) for a review of translational and clinical studies in human patients.


Axon Compound action potential Conduction Demyelination Experimental allergic neuritis Ion channel Myelin Nerve Neuropathy Schwann cell 



Acute motor axonal neuropathy


Adenine monophosphate


Adenine triphosphate


Cyclic adenine triphosphate


Compound action potential


Contactin-associated glycoprotein


Compound muscle action potential




Experimental allergic neuritis


Extracellular fluid




Ganglioside GD1a


Ganglioside GM1


Ganglioside GT1b


Hyperpolarization-activated cyclic-nucleotide-gated


Heparin-sulfate proteoglycan


Voltage-gated potassium channel nomenclature


Long-duration and large current generated by calcium channels


Membrane attack complex


Myelin-associated glycoprotein


Multifocal motor neuropathy


Voltage-gated sodium channel nomenclature




Nitric oxide


Neuronal cell adhesion molecule


Protein zero


Protein two


Purinergic receptor nomenclature


Peripheral myelin protein twenty-two


Transient and tiny current generated by calcium channels


  1. Baker MD (2002) Electrophysiology of mammalian Schwann cells. Prog Biophys Mol Biol 78:83–103PubMedCrossRefPubMedCentralGoogle Scholar
  2. Baker M, Bostock H, Grafe P, Martius P (1987) Function and distribution of three types of rectifying channel in rat spinal root myelinated axons. J Physiol 383:45–67PubMedPubMedCentralCrossRefGoogle Scholar
  3. Balice-Gordon RJ, Bone LJ, Scherer SS (1998) Functional gap junctions in the Schwann cell myelin sheath. J Cell Biol 142:1095–1104PubMedPubMedCentralCrossRefGoogle Scholar
  4. Barrett EF, Barrett JN (1982) Intracellular recording from vertebrate myelinated axons: mechanism of the depolarizing afterpotential. J Physiol 323:117–144PubMedPubMedCentralCrossRefGoogle Scholar
  5. Berthold CH, Rydmark M (1995) Morphology of normal peripheral axons. In: Waxman SG, Kocsis JD, Stys PK (eds) The Axon. Oxford University Press, New York, pp 13–48CrossRefGoogle Scholar
  6. Blight AR (1985) Computer simulation of action potentials and afterpotentials in mammalian myelinated axons: the case for a lower resistance myelin sheath. Neurosci 15:13–31CrossRefGoogle Scholar
  7. Bostock H, Grafe P (1985) Activity-dependent excitability changes in normal and demyelinated rat spinal root axons. J Physiol 365:239–257PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bostock H, Rothwell JC (1997) Latent addition in motor and sensory fibres of human peripheral nerve. J Physiol 498(1):277–294PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bostock H, Sears TA (1978) The internodal axon membrane: electrical excitability and continuous conduction in segmental demyelination. J Physiol 280:273–301PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bostock H, Sears TA, Sherratt RM (1981) The effects of 4-aminopyridine and tetraethylammonium ions on normal and demyelinated mammalian nerve fibers. J Physiol 313:301–315PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bostock H, Baker M, Reid G (1991) Changes in excitability of human motor axons underlying post-ischaemic fasciculations: evidence for two stable states. J Physiol 441:537–557PubMedPubMedCentralCrossRefGoogle Scholar
  12. Brismar T (1991) Electrical properties of isolated demyelinated rat nerve fibers. Acta Physiol Scand 113:161–166CrossRefGoogle Scholar
  13. Caldwell JH, Schaller KL, Lasher RS, Peles E, Levinson SR (2000) Sodium channel Nav1.6 is localized at nodes of Ranvier, dendrites, and synapses. PNAS 97:5616–5620PubMedCrossRefPubMedCentralGoogle Scholar
  14. Clark AJ, Kaller MS, Galino J, Willison HJ, Rinaldi S, Bennett DLH (2017) Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination. Brain 140:898–913PubMedPubMedCentralCrossRefGoogle Scholar
  15. Court FA, Hendriks WTJ, MacGillavry HD, Alvarez J, Van Minnen J (2008) Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J Neurosci 28:11024–11029PubMedPubMedCentralCrossRefGoogle Scholar
  16. David G, Barrett JN, Barrett EF (1993) Activation of internodal potassium conductance in rat myelinated axons. J Physiol 472:177–202PubMedPubMedCentralCrossRefGoogle Scholar
  17. Frankenhaeuser B, Moore LE (1963) The effect of temperature on the sodium and potassium permeability changes in myelinated nerve fibres of Xenopus laevis. J Physiol 169:431–437PubMedPubMedCentralCrossRefGoogle Scholar
  18. Franssen H, Straver DCG (2013) Pathophysiology of immune-mediated demyelinating neuropathies – part I: neuroscience. Muscle Nerve 48:851–864PubMedCrossRefPubMedCentralGoogle Scholar
  19. Franssen H, Straver DCG (2014) Pathophysiology of immune-mediated demyelinating neuropathies – part II: neurology. Muscle Nerve 49:4–20PubMedCrossRefGoogle Scholar
  20. Franssen H, Gebbink TA, Wokke JH, Van den Berg LH, Van Schelven LJ (2010) Is cold paresis related to axonal depolarization? J Periph Nerv Syst 15:227–237CrossRefGoogle Scholar
  21. Gong Y, Tagawa Y, Lunn MPT, Laroy W, Heffer-Lauc M, Li CY, Griffin JW, Schnaar RL, Sheikh KA (2002) Localization of major gangliosides in the PNS: implications for immune neuropathies. Brain 125:2491–2506PubMedCrossRefPubMedCentralGoogle Scholar
  22. Grafe P, Mayer C, Takigawa T, Kamleiter M, Sanchez-Brandelik R (1999) Confocal calcium imaging reveals an inotropic P2 nucleotide receptor in the paranodal membrane of rat Schwann cells. J Physiol 515:377–383PubMedPubMedCentralCrossRefGoogle Scholar
  23. Hirota N, Kaji R, Bostock H, Shindo K, Kawasaki T, Mizutani K, Oka N, Kohara N, Saida T, Kimura J (1997) The physiological effect of anti-GM1 antibodies on saltatory conduction and transmembrane currents in single motor axons. Brain 120:2159–2169PubMedCrossRefPubMedCentralGoogle Scholar
  24. IUPHAR (2005) Compendium of voltage-gated ion channels. Pharmacol Rev 57:385–540CrossRefGoogle Scholar
  25. Jonas P, Koh DS, Kampe K, Hermsteiner M, Vogel W (1991) ATP-sensitive and Ca-activated K channels in vertebrate axons: novel links between metabolism and excitability. Pflügers Arch 418:68–73PubMedCrossRefPubMedCentralGoogle Scholar
  26. Kaji R, Sumner AJ (1989) Ouabain reverses conduction disturbances in single demyelinated nerve fibers. Neurology 39:1364–1368PubMedCrossRefPubMedCentralGoogle Scholar
  27. Kapoor R, Davies M, Blaker PA, Hall SM, Smith KJ (2003) Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann Neurol 53:174–180PubMedCrossRefPubMedCentralGoogle Scholar
  28. Koles ZJ, Rasminsky M (1972) A computer simulation of conduction in demyelinated nerve fibres. J Physiol 227:351–364PubMedPubMedCentralCrossRefGoogle Scholar
  29. Lonigro A, Devaux JJ (2009) Disruption of neurofascin and gliomedin at nodes of Ranvier precedes demyelination in experimental allergic neuritis. Brain 132:260–273PubMedCrossRefGoogle Scholar
  30. Low PA, McLeod JG (1997) Refractory period, conduction of trains of impulses, and effect of temperature on conduction in chronic hypertrophic neuropathy. J Neurol Neurosurg Psychiatry 40:434–447CrossRefGoogle Scholar
  31. Manso C, Querol L, Mekaouche M, Illa I, Devaux JJ (2016) Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain 139:1700–1712PubMedCrossRefGoogle Scholar
  32. Martini R (2001) The effect of myelinating Schwann cells on axons. Muscle Nerve 24:456–466PubMedCrossRefPubMedCentralGoogle Scholar
  33. McGonigal R, Rowan EG, Greenshields KN, Halstead SK, Humphreys PD, Rother RP, Furukawa K, Willison HJ (2010) Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain 133:1944–1960PubMedCrossRefGoogle Scholar
  34. Mi H, Deerinck TJ, Ellisman MH, Schwarz TL (1995) Differential distribution of closely related potassium channels in rat Schwann cells. J Neurosci 15:3761–3774PubMedPubMedCentralCrossRefGoogle Scholar
  35. Novakovic SD, Levinson SR, Schachner M, Shrager P (1998) Disruption and reorganization of sodium channels in experimental allergic neuritis. Muscle Nerve 21:1019–1032PubMedCrossRefGoogle Scholar
  36. Nygren A, Halter JA (1999) A general approach to modeling conduction and concentration dynamics in excitable cells of concentric cylindrical geometry. J Theor Biol 199:329–358PubMedCrossRefPubMedCentralGoogle Scholar
  37. Ogawa-Goto K, Funamoto N, Abe T, Nagashima K (1990) Different ceramide compositions of gangliosides between human motor and sensory nerves. J Neurochem 55:1486–1493PubMedCrossRefGoogle Scholar
  38. Paparounas K, O’Hanlon GM, O’Leary CP, Rowan EG, Willison HJ (1999) Anti-ganglioside antibodies can bind peripheral nerve nodes of Ranvier and activate the complement cascade without inducing acute conduction block in vitro. Brain 122:807–816PubMedCrossRefPubMedCentralGoogle Scholar
  39. Rash JE, Vanderpool KG, Yasumura T, Hickman J, Beatty JT, Nagy JI (2016) Kv1 channels identified in rodent myelinated axons, linked to Cx29 in innermost myelin: support for electrically active myelin in mammalian saltatory conduction. J Neurophysiol 115:1836–1859PubMedPubMedCentralCrossRefGoogle Scholar
  40. Rasminsky M (1973) The effects of temperature on conduction in demyelinated single nerve fibers. Arch Neurol 28:287–292PubMedCrossRefGoogle Scholar
  41. Rasminsky M, Sears TA (1972) Internodal conduction in undissected demyelinated nerve fibers. J Physiol 227:323–350PubMedPubMedCentralCrossRefGoogle Scholar
  42. Reid G, Scholz A, Bostock H, Vogel W (1999) Human axons contain at least five types of voltage-dependent potassium channel. J Physiol 518(3):681–696PubMedPubMedCentralCrossRefGoogle Scholar
  43. Ritchie JM (1995) Physiology of axons. In: Waxman SG, Kocsis JD, Stys PK (eds) The Axon. Oxford University Press, New York, pp 68–96CrossRefGoogle Scholar
  44. Saida K, Sumner AJ, Saida T, Brown MJ, Silberberg DH (1980) Antiserum-mediated demyelination: relationship between remyelination and functional recovery. Ann Neurol 8:12–24PubMedCrossRefGoogle Scholar
  45. Salzer JL, Brophy PJ, Peles E (2008) Molecular domains of myelinated axons in the peripheral nervous system. Glia 56:1532–1540PubMedCrossRefGoogle Scholar
  46. Santoro M, Uncini A, Corbo M, Staugaitis SM, Thomas FP, Hays AP, Latov N (1992) Experimental conduction block induced by serum from a patient with anti-GM1 antibodies. Ann Neurol 31:385–390PubMedCrossRefGoogle Scholar
  47. Scherer SS, Arroyo EJ (2002) Recent progress on the molecular organization of myelinated axons. J Periph Nerv Syst 7:1–12CrossRefGoogle Scholar
  48. Schwarz JR, Eikhof G (1987) Na currents and action potentials in rat myelinated nerve fibers at 20 and 37 degrees C. Pflügers Arch 409:569–577PubMedCrossRefPubMedCentralGoogle Scholar
  49. Schwarz JR, Corrette BJ, Mann K, Wiethölter H (1991) Changes of ionic channel distribution in myelinated nerve fibers from rats with experimental allergic neuritis. Neurosci Lett 122:205–209PubMedCrossRefPubMedCentralGoogle Scholar
  50. Schwarz JR, Reid G, Bostock H (1995) Action potentials and membrane currents in the human node of Ranvier. Pflügers Arch 430:283–292PubMedCrossRefPubMedCentralGoogle Scholar
  51. Sheikh KA, Deerinck TJ, Ellisman MH, Griffin JW (1999) The distribution of ganglioside-like moieties in peripheral nerves. Brain 122:449–460PubMedCrossRefPubMedCentralGoogle Scholar
  52. Smith KJ, Bostock H, Hall SM (1982) Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline. J Neurol Sci 54:13–31PubMedCrossRefPubMedCentralGoogle Scholar
  53. Sumner AJ, Saida K, Saida T, Silberberg DH, Asbury AK (1982) Acute conduction block associated with experimental antiserum-mediated demyelination of peripheral nerve. Ann Neurol 11:469–477PubMedCrossRefPubMedCentralGoogle Scholar
  54. Susuki K, Rasband MN, Tohyama K, Koibuchi K, Okamoto S, Funakoshi K, Hirata K, Baba H, Yuki N (2007) Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci 27:3956–3967PubMedPubMedCentralCrossRefGoogle Scholar
  55. Susuki K, Yuki N, Schafer DP, Hirata K, Zhang G, Funakoshi K, Rasband MN (2012) Dysfunction of nodes of Ranvier: a mechanism for anti-ganglioside antibody-mediated neuropathies. Exp Neurol 233:534–542PubMedCrossRefPubMedCentralGoogle Scholar
  56. Takigawa T, Yasuda H, Kikkawa R, Shigata Y, Saida T, Kitsato H (1995) Antibodies against GM1 ganglioside affect K+ and Na+ currents in isolated rat myelinated nerve fibers. Ann Neurol 37:436–442PubMedCrossRefPubMedCentralGoogle Scholar
  57. Tasaki I (1955) New measurements of the capacity and the resistance of the myelin sheath and the nodal membrane of the isolated frog nerve fiber. Am J Phys 181:639–650CrossRefGoogle Scholar
  58. Von Reyn CR, Spaethling JM, Mesfin MN, Ma M, Neumar RW, Smith DH, Siman R, Meaney DF (2009) Calpain mediates proteolysis of the voltage-gated sodium channel α-subunit. J Neurosci 29:10350–10356CrossRefGoogle Scholar
  59. Waxman SG (2006) Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 7:932–941PubMedCrossRefGoogle Scholar
  60. Waxman SG, Kocsis JD, Black JA (1995) Pathophysiology of demyelinated axons. In: Waxman SG, Kocsis JD, Stys PK (eds) The Axon. Oxford University Press, New York, pp 438–461CrossRefGoogle Scholar
  61. Wilson GF, Chiu SY (1990) Ion channels in axon and Schwann cell membranes at paranodes of mammalian myelinated fibers studied with patch clamp. J Neurosci 10:3263–3274PubMedPubMedCentralCrossRefGoogle Scholar
  62. Wu LMN, Williams A, Delaney A, Sherman DL, Brophy PJ (2012) Increasing internodal distance in myelinated nerves accelerates nerve conduction to a flat maximum. Curr Biol 22:1957–1961PubMedPubMedCentralCrossRefGoogle Scholar
  63. Zhang Z, David G (2016) Stimulation-induced Ca2+ influx at nodes of Ranvier in mouse peripheral motor axons. J Physiol 594(1):39–57PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Neurology and Clinical Neurophysiology, Department of Neuromuscular Disorders, Brain Center Rudolf MagnusUniversity Medical Center UtrechtUtrechtThe Netherlands

Personalised recommendations