Journal of Neurocytology

, Volume 20, Issue 12, pp 969–981 | Cite as

Structure and function of the neuromuscular junction in young adultmdx mice

  • P. R. Lyons
  • C. R. Slater


Dystrophin, the protein product of the gene responsible for X-linked muscular dystrophies, shares structural features with the cytoskeletal proteins spectrin and α-actinin. Like spectrin, it is localized at the cytoplasmic surface of the sarcolemma and is particularly concentrated in the subsynaptic region of the neuromuscular junction.Mdx mice have a profound deficiency of dystrophin and develop a necrotizing myopathy in the first weeks of life. Abnormalities of the neuromuscular junction, including a redistribution of postsynaptic molecules and reduction in synaptic folding, are also observed. We have studied these mice to see whether the lack of dystrophin has a specific effect on the structure and function of their neuromuscular junctions.

Using a fore-limb muscle from 8 week oldmdx mice we confirm the previously described postsynaptic structural changes and in addition show that many nerve terminals are abnormally complex. We demonstrate that these structural abnormalities are found exclusively at neuromuscular junctions on regenerated muscle fibres. Despite these structural abnormalities, miniature endplate potential frequency, the quantal content of endplate potentials, the amplitude and time course of miniature endplate currents and the number of acetylcholine receptors at the postsynaptic membrane are normal inmdx mice of this age. We conclude that in themdx mouse the absence of dystrophin from the postsynaptic membrane has little direct effect on the function of the neuromuscular junction but that degeneration and regeneration of muscle fibres leads to remodelling of both its pre- and postsynaptic components.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Anderson, C. R. &Stevens, C. F. (1973) Voltage clamp analysis of acetylcholine produced end-plate current fluctuations at the frog neuromuscular junction.Journal of Physiology 235, 655–91.PubMedGoogle Scholar
  2. Bradley, S., Lyons, P. R. &Slater, C., R. (1989) The epitrochleoanconeus muscle (ETA) of the mouse: a useful muscle for the study of motor innervation in vitro.Journal of Physiology 415, 3P.Google Scholar
  3. Bulfield, G., Siller, W. G., Wight, P. A. &Moore, K. J. (1984) X chromosome-linked muscular dystrophy (mdx) in the mouse.Proceedings of the National Academy of Sciences (USA) 81, 1189–92.Google Scholar
  4. Campbell, K. P. &Kahl, S. D. (1989) Association of dystrophin and an integral membrane glycoprotein.Nature 338, 259–62.PubMedGoogle Scholar
  5. Carnwath, J. W. &Shotton, D. M. (1987) Muscular dystrophy in themdx mouse: histopathology of the soleus and extensor digitorum longus muscles.Journal of the Neurological Sciences 80, 39–54.PubMedGoogle Scholar
  6. Coërs, C. &Woolf, A. L. (1959)The Innervation of Muscle, a Biopsy Study. Oxford: Blackwell Scientific Publications.Google Scholar
  7. Colquhoun, D., Large, W. A. &Rang, H. P. (1977) An analysis of the action of a false transmitter at the neuromuscular junction.Journal of Physiology 266, 464–6.Google Scholar
  8. Coulton, G. R., Morgan, J. E., Partridge, T. A. &Sloper, J. C. (1988) Themdx mouse skeletal muscle myopathy: I. A histological, morphometric and biochemical investigation.Neuropathology and Applied Neurobiology 14, 53–70.PubMedGoogle Scholar
  9. Cull-Candy, S. G., Miledi, R., Trautmann, A. &Uchitel, O. D. (1980) On the release of transmitter at normal, myasthenia gravis and myasthenic syndrome affected human end-plates.Journal of Physiology 299, 621–38.PubMedGoogle Scholar
  10. Duchen, L. W., Excell, B. J., Patel, R. &Smith, B. (1974) Changes in motor end-plates resulting from fibre necrosis and regeneration: a light and electron microscopic study of the effects of the depolarizing fraction (cardiotoxin) of Dendroaspis jamesoni vemon.Journal of the Neurological Sciences 21, 391–417.PubMedGoogle Scholar
  11. Engel, A. G. &Santa, T. (1971) Histometric analysis of the ultrastructure of the neuromuscular junction in myasthenia gravis and in the myasthenic syndrome.Annals of the New York Academy of Science 183, 46–63.Google Scholar
  12. Fardeau, M., Tome, F. M. S., Collin, H., Augier, N., Pons, N. &Leger, J. (1990) Presence of dystrophin-like protein at the neuromuscular junctions in Duchenne muscular dystrophy and in themdx mutant mouse.Comptes Rendus de l'Academie des Sciences (Paris) 311, 197–204.Google Scholar
  13. Fawcett, P. R. W., Schofield, I. S., Slater, C. R. &Walls, T. J. (1978) Structure and function of the neuromuscular junction in human neuromuscular diseases.Journal of Physiology 391, 12P.Google Scholar
  14. Ferry, C. B. &Kelly, S. S. (1988) The nature of the presynaptic effects of (+)-tubocurarine at the mouse neuromuscular junction.Journal of Physiology 403, 425–37.PubMedGoogle Scholar
  15. Glavinovic, M. I. (1979) Presynaptic action of curare.Journal of Physiology 290, 499–506.PubMedGoogle Scholar
  16. Grubb, B. D., Harris, J. B. &Schofield, I. S. (1991) Neuromuscular transmission at newly formed neuromuscular junctions in the regenerating soleus muscle of the rat.Journal of Physiology,441, 405–21.PubMedGoogle Scholar
  17. Harriman, D. G. F. (1976) A comparison of fine structure of motor end-plates in Duchenne dystrophy and in human neurogenic diseases.Journal of the Neurological Sciences 28, 233–47.PubMedGoogle Scholar
  18. Harris, C. (1954) The morphology of the myoneural junction as influenced by neurotoxic drugs.American Journal of Pathology 30, 501–19.PubMedGoogle Scholar
  19. Harris, J. B. &Ribchester, R. R. (1979) The relationship between end-plate size and transmitter release in normal and dystrophic muscles of the mouse.Journal of Physiology 296, 245–65.PubMedGoogle Scholar
  20. Hodgkin, A. L. &Rushton, W. A. H. (1946) The electrical constants of a crustacean nerve fibre.Proceedings of the Royal Society of London B 133, 444–79.Google Scholar
  21. Hoffman, E. P., Brown, R. H. Jr. &Kunkel, L. M. (1987) Dystrophin: the protein product of the Duchenne muscular dystrophy locus.Cell 51, 919–28.PubMedGoogle Scholar
  22. Hollingsworth, S., Marshall, M. W. &Robson, E. (1990) Excitation contraction coupling in normal andmdx mice.Muscle and Nerve 13, 16–20.PubMedGoogle Scholar
  23. Hubbard, J. I. &Wilson, D. F. (1973) Neuromuscular transmission in mammalian preparation in the absence of blocking drugs and the effect of d-tubocurarine.Journal of Physiology 228, 307–25.PubMedGoogle Scholar
  24. Jasmin, B. J., Cartaud, A., Ludosky, M. A., Changeux, J. P. &Cartaud, J. (1990) Asymmetric distribution of dystrophin in developing and adult Torpedo marmorata electrocyte: evidence for its association with the acetylcholine receptor-rich membrane.Proceedings of the National Academy of Sciences (USA) 87, 3938–41.Google Scholar
  25. Karnovsky, M. J. (1965) A formaldehyde-glutaraldehyde fixative of high osmolality for use in electron microscopy.Journal of Cell Biology 27, 137A.Google Scholar
  26. Karnovsky, M. J. &Roots, I. A. (1964) ‘Direct colouring’ thiocholine method for cholinesterases.Journal of Histochemistry and Cytochemistry 112, 219–21.Google Scholar
  27. Karpati, G., Carpenter, S. &Prescott, S. (1988) Small-calibre skeletal muscle fibres do not suffer necrosis inmdx mouse dystrophy.Muscle and Nerve 11, 795–803.PubMedGoogle Scholar
  28. Koenig, M., Monaco, A. P. &Kunkel, L. M. (1988) The complete sequence of dystrophin predicts a rod-shaped cytoskeletal protein.Cell 53, 219–26.PubMedGoogle Scholar
  29. Korneliussen, H. (1972) Ultrastructure of normal and stimulated motor endplates.Zeitschrift für Zellforschung 130, 28–57.Google Scholar
  30. Liley, A. W. (1956) An investigation of spontaneous activity at the neuromuscular junction of the rat.Journal of Physiology 132, 650–66.PubMedGoogle Scholar
  31. Martin, A. R. (1955) A further study of the statistical composition of the end-plate potential.Journal of Physiology 130, 114–22.PubMedGoogle Scholar
  32. Miike, T., Miyatake, M., Zhao, J., Yoshioka, K. &Uchino, M. (1989) Immunohistochemical dystrophin reaction in synaptic regions.Brain and Development (Tokyo) 11, 344–6.Google Scholar
  33. Nagel, A., Lenmann-Horn, F. &Engel, A. G. (1990) Neuromuscular transmission in themdx mouse.Muscle and Nerve 13, 742–9.PubMedGoogle Scholar
  34. Nakane, P. K. &Kowaoi, A. (1974) Peroxidase labelled antibody, a new method of conjugation.Journal of Histochemistry and Cytochemistry 5, 1280–3.Google Scholar
  35. Quastel, D. M. J. &Linder, T. M. (1975) Pre- and post-synaptic actions of central depressants at the mammalian neuromuscular junction.Progress in Anesthesiology 1, 157–68.Google Scholar
  36. Sakakibara, H., Engel, A. G. &Lambert, E. H. (1977) Duchenne dystrophy: ultrastructural localization of the acetylcholine receptor and intracellular microelectrode studies of neuromuscular transmission.Neurology 27, 741–5.PubMedGoogle Scholar
  37. Salpeter, M. M. (1987) Vertebrate neuromuscular junctions: general morphology, molecular organization, and functional consequences. InThe Vertebrate Neuromuscular Junction (edited bySalpeter, M. M.), pp. 35–43. New York, Alan R. Liss.Google Scholar
  38. Shimizu, T., Matsumura, K., Sunada, Y. &Mannen, T. (1989) Dense immunostaining of both neuromuscular and myotendon junctions with an anti-dystrophin antibody.Biomedical Research 10, 405–9.Google Scholar
  39. Sicinski, P., Geng, Y., Ryder Cook, A. S., Barnard, E. A., Darlison, M. G. &Barnard, P. J. (1989) The molecular basis of muscular dystrophy in themdx mouse: a point mutation.Science 244, 1578–80.PubMedGoogle Scholar
  40. Slater, C. R. (1982) Postnatal maturation of nerve-muscle junctions in the hindlimb muscles of the mouse.Developmental Biology 94, 11–22.PubMedGoogle Scholar
  41. Strum, J. M. &Hall-Craggs, E. C. B. (1982) A method demonstrating motor endplates for light and electron microscopy.Journal of Neuroscience Methods 6, 305–9.PubMedGoogle Scholar
  42. Tanabe, Y., Esaki, K. &Nomura, T. (1986) Skeletal muscle pathology in X chromosome-linked muscular dystrophy (mdx) mouse.Acta Neuropathologica (Berlin) 69, 91–5.Google Scholar
  43. Torres, L. F. &Duchen, L. W. (1987) The mutantmdx: inherited myopathy in the mouse. Morphological studies of nerves, muscles and end-plates.Brain 110, 269–99.PubMedGoogle Scholar
  44. Tsuji, S. &Tobin-Gros, C. (1980) A simple silver nitrate impregnation of the nerve fibres with preservation of acetylcholinesterase activity at the motor end-plate.Experientia 36, 1317–19.PubMedGoogle Scholar
  45. Zubrzycka-Gaarn, E. E., Bulman, D. E., Karpati, G., Burghes, A. H., Belfall, B., Klamut, H. J., Talbot, J., Hodges, R. S., Ray, P. N. &Worton, R. G. (1988) The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle.Nature 333, 466–9.PubMedGoogle Scholar

Copyright information

© Chapman and Hall Ltd 1991

Authors and Affiliations

  • P. R. Lyons
    • 1
  • C. R. Slater
    • 1
  1. 1.The Muscular Dystrophy Group LaboratoriesNewcastle General HospitalNewcastle upon TyneUK

Personalised recommendations