Neuromuscular Junction Physiology and Pathophysiology

Chapter
Part of the Current Clinical Neurology book series (CCNEU)

Abstract

The neuromuscular junction (NMJ) is a cholinergic synapse that connects a motor neuron to a skeletal muscle fiber. To enable sustained tetanic contraction of skeletal muscle, the NMJ must reliably transmit the impulses from the presynaptic motor neuron to the postsynaptic muscle fiber. This seemingly simple task is enabled by the existence of a complex system of pre- and postsynaptic structural subcellular specializations and functional molecular machineries. These are responsible for (1) the development and maintenance of the synaptic structure, (2) the controlled presynaptic release of the neurotransmitter acetylcholine, and (3) the postsynaptic translation of this chemical message into an excitatory electrical response. The many factors in this synaptic system all have their inherent risks and vulnerabilities, e.g., in autoimmunity or upon intoxication. The resulting malfunctions compromise successful neuromuscular transmission and may lead to disturbances of muscle contraction. This chapter describes the normal NMJ structure and electrophysiological function and briefly discusses the pathophysiology occurring in myasthenia gravis (with autoantibodies against postsynaptic acetylcholine receptors) and some of the related NMJ synaptopathies.

Keywords

Acetylcholine receptor Autoimmunity Electrophysiology Endplate Endplate potential Fatigue Muscle-specific kinase Myasthenia gravis Neuromuscular junction Neurotransmitter Safety factor Skeletal muscle Synapse 

Notes

Acknowledgments

The author gratefully acknowledges support by the Prinses Beatrix Spierfonds, Stichting Spieren voor Spieren, and L’Association Française contre les myopathies.

References

  1. 1.
    Slater CR. Structural factors influencing the efficacy of neuromuscular transmission. Ann N Y Acad Sci. 2008;1132:1–12.CrossRefPubMedGoogle Scholar
  2. 2.
    Darabid H, Perez-Gonzalez AP, Robitaille R. Neuromuscular synaptogenesis: coordinating partners with multiple functions. Nat Rev Neurosci. 2014;15:703–18.CrossRefPubMedGoogle Scholar
  3. 3.
    Kang H, Tian L, Mikesh M, Lichtman JW, Thompson WJ. Terminal Schwann cells participate in neuromuscular synapse remodeling during reinnervation following nerve injury. J Neurosci. 2014;34:6323–33.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sudhof TC. Neurotransmitter release: the last millisecond in the life of a synaptic vesicle. Neuron. 2013;80:675–90.CrossRefPubMedGoogle Scholar
  5. 5.
    Nishimune H. Active zones of mammalian neuromuscular junctions: formation, density, and aging. Ann N Y Acad Sci. 2012;1274:24–32.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen J, Mizushige T, Nishimune H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol. 2012;520:434–52.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Uchitel OD, Protti DA, Sanchez V, Cherksey BD, Sugimori M, Llinas R. P-type voltage-dependent calcium channel mediates presynaptic calcium influx and transmitter release in mammalian synapses. Proc Natl Acad Sci U S A. 1992;89:3330–3.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kaja S, van de Ven RC, van Dijk JG, Verschuuren JJ, Arahata K, Frants RR, et al. Severely impaired neuromuscular synaptic transmission causes muscle weakness in the Cacna1a-mutant mouse rolling Nagoya. Eur J Neurosci. 2007;25:2009–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Chen J, Billings SE, Nishimune H. Calcium channels link the muscle-derived synapse organizer laminin beta2 to Bassoon and CAST/Erc2 to organize presynaptic active zones. J Neurosci. 2011;31:512–25.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Chamberlain LH, Burgoyne RD, Gould GW. SNARE proteins are highly enriched in lipid rafts in PC12 cells: implications for the spatial control of exocytosis. Proc Natl Acad Sci U S A. 2001;98:5619–24.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Davies A, Douglas L, Hendrich J, Wratten J, Tran Van MA, Foucault I, et al. The calcium channel alpha2delta-2 subunit partitions with CaV2.1 into lipid rafts in cerebellum: implications for localization and function. J Neurosci. 2006;26:8748–57.CrossRefPubMedGoogle Scholar
  12. 12.
    Plomp JJ, Willison HJ. Pathophysiological actions of neuropathy-related anti-ganglioside antibodies at the neuromuscular junction. J Physiol. 2009;587:3979–99.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Massoulie J, Millard CB. Cholinesterases and the basal lamina at vertebrate neuromuscular junctions. Curr Opin Pharmacol. 2009;9:316–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Singhal N, Martin PT. Role of extracellular matrix proteins and their receptors in the development of the vertebrate neuromuscular junction. Dev Neurobiol. 2011;71:982–1005.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Rogers RS, Nishimune H. The role of laminins in the organization and function of neuromuscular junctions. Matrix Biol. 2017;57–58:86–105.CrossRefPubMedGoogle Scholar
  16. 16.
    Wu H, Lu Y, Shen C, Patel N, Gan L, Xiong WC, et al. Distinct roles of muscle and motoneuron LRP4 in neuromuscular junction formation. Neuron. 2012;75:94–107.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bruneau E, Sutter D, Hume RI, Akaaboune M. Identification of nicotinic acetylcholine receptor recycling and its role in maintaining receptor density at the neuromuscular junction in vivo. J Neurosci. 2005;25:9949–59.CrossRefPubMedGoogle Scholar
  18. 18.
    Martinez P, Pires-Oliveira M, Akaaboune M. PKC and PKA regulate AChR dynamics at the neuromuscular junction of living mice. PLoS One. 2013;8:e81311.CrossRefGoogle Scholar
  19. 19.
    Vautrin J, Mambrini J. Synaptic current between neuromuscular junction folds. J Theor Biol. 1989;140:479–98.CrossRefPubMedGoogle Scholar
  20. 20.
    Ruff RL, Lennon VA. End-plate voltage-gated sodium channels are lost in clinical and experimental myasthenia gravis. Ann Neurol. 1998;43:370–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Grady RM, Teng H, Nichol MC, Cunningham JC, Wilkinson RS, Sanes JR. Skeletal and cardiac myopathies in mice lacking utrophin and dystrophin: a model for Duchenne muscular dystrophy. Cell. 1997;90:729–38.CrossRefPubMedGoogle Scholar
  22. 22.
    Pilgram GS, Potikanond S, Baines RA, Fradkin LG, Noordermeer JN. The roles of the dystrophin-associated glycoprotein complex at the synapse. Mol Neurobiol. 2010;41:1–21.CrossRefPubMedGoogle Scholar
  23. 23.
    van der Pijl EM, van Putten M, Niks EH, Verschuuren JJ, Aartsma-Rus A, Plomp JJ. Characterization of neuromuscular synapse function abnormalities in multiple Duchenne muscular dystrophy mouse models. Eur J Neurosci. 2016;43:1623–35.CrossRefPubMedGoogle Scholar
  24. 24.
    Ghazanfari N, Fernandez KJ, Murata Y, Morsch M, Ngo ST, Reddel SW, et al. Muscle specific kinase: organiser of synaptic membrane domains. Int J Biochem Cell Biol. 2011;43:295–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Wu H, Xiong WC, Mei L. To build a synapse: signaling pathways in neuromuscular junction assembly. Development. 2010;137:1017–33.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Chen PJ, Martinez-Pena y Valenzuela I, Aittaleb M, Akaaboune M. AChRs are essential for the targeting of rapsyn to the postsynaptic membrane of NMJs in living mice. J Neurosci. 2016;36:5680–5.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gautam M, Noakes PG, Mudd J, Nichol M, Chu GC, Sanes JR, et al. Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature. 1995;377:232–6.CrossRefPubMedGoogle Scholar
  28. 28.
    Escher P, Lacazette E, Courtet M, Blindenbacher A, Landmann L, Bezakova G, et al. Synapses form in skeletal muscles lacking neuregulin receptors. Science. 2005;308:1920–3.CrossRefPubMedGoogle Scholar
  29. 29.
    Jaworski A, Burden SJ. Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived Neuregulin-1. J Neurosci. 2006;26:655–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Rimer M. Neuregulins at the neuromuscular synapse: past, present, and future. J Neurosci Res. 2007;85:1827–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Schmidt N, Akaaboune M, Gajendran N, Martinez P, Wakefield S, Thurnheer R, et al. Neuregulin/ErbB regulate neuromuscular junction development by phosphorylation of alpha-dystrobrevin. J Cell Biol. 2011;195:1171–84.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rebbeck RT, Karunasekara Y, Board PG, Beard NA, Casarotto MG, Dulhunty AF. Skeletal muscle excitation-contraction coupling: who are the dancing partners? Int J Biochem Cell Biol. 2014;48:28–38.CrossRefPubMedGoogle Scholar
  33. 33.
    Lang B, Makuch M, Moloney T, Dettmann I, Mindorf S, Probst C, et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry. 2017;88:353–61.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Park SB, Lin CS, Krishnan AV, Simon NG, Bostock H, Vincent A, et al. Axonal dysfunction with voltage gated potassium channel complex antibodies. Exp Neurol. 2014;261:337–42.CrossRefPubMedGoogle Scholar
  35. 35.
    Shillito P, Molenaar PC, Vincent A, Leys K, Zheng W, van den Berg RJ, et al. Acquired neuromyotonia: evidence for autoantibodies directed against K+ channels of peripheral nerves. Ann Neurol. 1995;38:714–22.CrossRefPubMedGoogle Scholar
  36. 36.
    van SA, Schreurs MW, Wirtz PW, Sillevis Smitt PA, Titulaer MJ. From VGKC to LGI1 and Caspr2 encephalitis: the evolution of a disease entity over time. Autoimmun Rev. 2016;15:970–4.CrossRefGoogle Scholar
  37. 37.
    Ranawaka UK, Lalloo DG, de Silva HJ. Neurotoxicity in snakebite—the limits of our knowledge. PLoS Negl Trop Dis. 2013;7:e2302.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Plomp JJ, van Kempen GT, De Baets MB, Graus YM, Kuks JB, Molenaar PC. Acetylcholine release in myasthenia gravis: regulation at single end-plate level. Ann Neurol. 1995;37:627–36.CrossRefPubMedGoogle Scholar
  39. 39.
    Samigullin D, Fatikhov N, Khaziev E, Skorinkin A, Nikolsky E, Bukharaeva E. Estimation of presynaptic calcium currents and endogenous calcium buffers at the frog neuromuscular junction with two different calcium fluorescent dyes. Front Synaptic Neurosci. 2014;6:29.PubMedGoogle Scholar
  40. 40.
    Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10:1098–107.CrossRefPubMedGoogle Scholar
  41. 41.
    Joubert B, Honnorat J. Autoimmune channelopathies in paraneoplastic neurological syndromes. Biochim Biophys Acta. 2015;1848:2665–76.CrossRefPubMedGoogle Scholar
  42. 42.
    Plomp JJ, Van den Maagdenberg AM, Molenaar PC, Frants RR, Ferrari MD, Mutant P. Q-type calcium channel electrophysiology and migraine. Curr Opin Investig Drugs. 2001;2:1250–60.PubMedGoogle Scholar
  43. 43.
    Maselli RA, Books W, Dunne V. Effect of inherited abnormalities of calcium regulation on human neuromuscular transmission. Ann N Y Acad Sci. 2003;998:18–28.CrossRefPubMedGoogle Scholar
  44. 44.
    Bullens RW, O’Hanlon GM, Wagner E, Molenaar PC, Furukawa K, Furukawa K, et al. Complex gangliosides at the neuromuscular junction are membrane receptors for autoantibodies and botulinum neurotoxin but redundant for normal synaptic function. J Neurosci. 2002;22:6876–84.PubMedGoogle Scholar
  45. 45.
    Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum neurotoxins: biology, pharmacology, and toxicology. Pharmacol Rev. 2017;69:200–35.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Milone M, Monaco ML, Evoli A, Servidei S, Tonali P. Ocular myasthenia: diagnostic value of single fibre EMG in the orbicularis oculi muscle. J Neurol Neurosurg Psychiatry. 1993;56:720–1.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Newland CF, Beeson D, Vincent A, Newsom-Davis J. Functional and non-functional isoforms of the human muscle acetylcholine receptor. J Physiol. 1995;489:767–78.Google Scholar
  48. 48.
    Sine SM. End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease. Physiol Rev. 2012;92:1189–234.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Bannister RA. Bridging the myoplasmic gap: recent developments in skeletal muscle excitation-contraction coupling. J Muscle Res Cell Motil. 2007;28:275–83.CrossRefPubMedGoogle Scholar
  50. 50.
    Plomp JJ, Morsch M, Phillips WD, Verschuuren JJ. Electrophysiological analysis of neuromuscular synaptic function in myasthenia gravis patients and animal models. Exp Neurol. 2015;270:41–54.CrossRefPubMedGoogle Scholar
  51. 51.
    McLachlan EM, Martin AR. Non-linear summation of end-plate potentials in the frog and mouse. J Physiol. 1981;311:307–24.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Choi BJ, Imlach WL, Jiao W, Wolfram V, Wu Y, Grbic M, et al. Miniature neurotransmission regulates Drosophila synaptic structural maturation. Neuron. 2014;82:618–34.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Flucher BE, Daniels MP. Distribution of Na+ channels and ankyrin in neuromuscular junctions is complementary to that of acetylcholine receptors and the 43 kd protein. Neuron. 1989;3:163–75.CrossRefPubMedGoogle Scholar
  54. 54.
    Wood SJ, Slater CR. The contribution of postsynaptic folds to the safety factor for neuromuscular transmission in rat fast- and slow-twitch muscles. J Physiol. 1997;500:165–76.Google Scholar
  55. 55.
    Wood SJ, Slater CR. Action potential generation in rat slow- and fast-twitch muscles. J Physiol. 1995;486:401–10.Google Scholar
  56. 56.
    Wood SJ, Slater CR. Safety factor at the neuromuscular junction. Prog Neurobiol. 2001;64:393–429.CrossRefPubMedGoogle Scholar
  57. 57.
    Eken T. Spontaneous electromyographic activity in adult rat soleus muscle. J Neurophysiol. 1998;80:365–76.CrossRefPubMedGoogle Scholar
  58. 58.
    Hennig R, Lomo T. Firing patterns of motor units in normal rats. Nature. 1985;314:164–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Niks EH, Kuks JB, Wokke JH, Veldman H, Bakker E, Verschuuren JJ, et al. Pre- and postsynaptic neuromuscular junction abnormalities in musk myasthenia. Muscle Nerve. 2010;42:283–8.CrossRefPubMedGoogle Scholar
  60. 60.
    Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023–36.CrossRefPubMedGoogle Scholar
  61. 61.
    Phillips WD, Vincent A. Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms. F1000Res. 2016;5:F1000.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Plomp JJ, van Kempen GT, Molenaar PC. Adaptation of quantal content to decreased postsynaptic sensitivity at single endplates in alpha-bungarotoxin-treated rats. J Physiol. 1992;458:487–99.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Tuzun E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev. 2013;12:904–11.CrossRefPubMedGoogle Scholar
  64. 64.
    Ruff RL, Lennon VA. How myasthenia gravis alters the safety factor for neuromuscular transmission. J Neuroimmunol. 2008;201–202:13–20.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ruff RL. Endplate contributions to the safety factor for neuromuscular transmission. Muscle Nerve. 2011;44:854–61.CrossRefPubMedGoogle Scholar
  66. 66.
    Huijbers MG, Zhang W, Klooster R, Niks EH, Friese MB, Straasheijm KR, et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci U S A. 2013;110:20783–8.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Verschuuren JJ, Huijbers MG, Plomp JJ, Niks EH, Molenaar PC, Martinez-Martinez P, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev. 2013;12:918–23.CrossRefPubMedGoogle Scholar
  68. 68.
    Cole RN, Reddel SW, Gervasio OL, Phillips WD. Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol. 2008;63:782–9.CrossRefPubMedGoogle Scholar
  69. 69.
    Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, et al. Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain. 2012;135:1081–101.CrossRefPubMedGoogle Scholar
  70. 70.
    Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology. 2004;62:1945–50.CrossRefPubMedGoogle Scholar
  71. 71.
    Shen C, Lu Y, Zhang B, Figueiredo D, Bean J, Jung J, et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest. 2013;123:5190–202.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Viegas S, Jacobson L, Waters P, Cossins J, Jacob S, Leite MI, et al. Passive and active immunization models of MuSK-Ab positive myasthenia: electrophysiological evidence for pre and postsynaptic defects. Exp Neurol. 2012;234:506–12.CrossRefPubMedGoogle Scholar
  73. 73.
    Morsch M, Reddel SW, Ghazanfari N, Toyka KV, Phillips WD. Pyridostigmine but not 3,4-diaminopyridine exacerbates ACh receptor loss and myasthenia induced in mice by muscle-specific kinase autoantibody. J Physiol. 2013;591:2747–62.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Plomp JJ. Trans-synaptic homeostasis at the myasthenic neuromuscular junction. Front Biosci (Landmark Ed). 2017;22:1033–51.CrossRefGoogle Scholar
  75. 75.
    Wang X, Pinter MJ, Rich MM. Reversible recruitment of a homeostatic reserve pool of synaptic vesicles underlies rapid homeostatic plasticity of quantal content. J Neurosci. 2016;36:828–36.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Barber CM, Isbister GK, Hodgson WC. Alpha neurotoxins. Toxicon. 2013;66:47–58.CrossRefPubMedGoogle Scholar
  77. 77.
    Barisic N, Chaouch A, Muller JS, Lochmuller H. Genetic heterogeneity and pathophysiological mechanisms in congenital myasthenic syndromes. Eur J Paediatr Neurol. 2011;15:189–96.CrossRefPubMedGoogle Scholar
  78. 78.
    Engel AG, Shen XM, Selcen D, Sine SM. Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment. Lancet Neurol. 2015;14:420–34.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyLeiden University Medical CentreLeidenThe Netherlands

Personalised recommendations