Skip to main content
SpringerLink
Log in

Assembly, plasticity and selective vulnerability to disease of mouse neuromuscular junctions

  • Published:
Journal of Neurocytology

Abstract

Although physiological differences among neuromuscular junctions (NMJs) have long been known, NMJs have usually been considered as one type of synapse, restricting their potential value as model systems to investigate mechanisms controlling synapse assembly and plasticity. Here we discuss recent evidence that skeletal muscles in the mouse can be subdivided into two previously unrecognized subtypes, designated FaSyn and DeSyn muscles. These muscles differ in the pattern of neuromuscular synaptogenesis during embryonic development. Differences between classes are intrinsic to the muscles, and manifest in the absence of innervation or agrin. The distinct rates of synaptogenesis in the periphery may influence processes of circuit maturation through retrograde signals. While NMJs on FaSyn and DeSyn muscles exhibit a comparable anatomical organization in postnatal mice, treatments that challenge synaptic stability result in nerve sprouting, NMJ remodeling, and ectopic synaptogenesis selectively on DeSyn muscles. This anatomical plasticity of NMJs diminishes greatly between 2 and 6 months postnatally. NMJs lacking this plasticity are lost selectively and very early on in mouse models of motoneuron disease, suggesting that disease-associated motoneuron dysfunction may fail to initiate maintenance processes at “non-plastic” NMJs. Transgenic mice overexpressing growth-promoting proteins in motoneurons exhibit greatly enhanced stimulus-induced sprouting restricted to DeSyn muscles, supporting the notion that anatomical plasticity at the NMJ is primarily controlled by processes in the postsynaptic muscle. The discovery that entire muscles in the mouse differ substantially in the anatomical plasticity of their synapses establishes NMJs as a uniquely advantageous experimental system to investigate mechanisms controlling synaptic rearrangements at defined synapses in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • AIGNER, L., ARBER, S., KAPFHAMMER, J. P., LAUX, T., SCHNEIDER, C., BOTTERI, F., BRENNER, H. R. & CARONI, P. (1995) Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell 83, 26–278.

    PubMed  Google Scholar 

  • AKAABOUNE, M., CULICAN, S. M., TURNEY, S. G. & LICHTMAN, J. W. (1999) Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286, 50–507.

    Google Scholar 

  • ANTONINI, A., GAGIOLINI, M. & STRYKER, M. P. (1999) Anatomical correlates of functional plasticity in mouse visual cortex. Journal of Neuroscience 19, 438–4406.

    PubMed  Google Scholar 

  • APEL, E. D., GLASS, D. J., MOSCOSO, L. M., YANCOPOULOS, G. D. & SANES, J. R. (1997) Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Neuron 18, 62–636.

    PubMed  Google Scholar 

  • BISBY, M. A. & TETZLAFF, W. (1992) Changes in cytoskeletal protein synthesis following axon injury and during axon regeneration. Molecular Neurobiology 6, 10–123.

    PubMed  Google Scholar 

  • BOMZE, H. M., BULSARA, K. R., ISKANDAR, B. J., CARONI, P. & SKENE, J. H. (2001) Spinal axon regeneration evoked by replacing two growth cone proteins in adult neurons. Nature Neuroscience 4, 3–43.

    PubMed  Google Scholar 

  • BRANDON, E. P., LIN, W., D'AMOUR, K. A., PIZZO, D. P., DOMINGUEZ, B., SUGIURA, Y., THODE, S., KO, C. P., THAL, L. J., GAGE, F. H. & LEE, K. F. (2003) Aberrant patterning of neuromuscular synapses in choline acetyltransferase-deficient mice. Journal of Neuroscience 23, 53–549.

    PubMed  Google Scholar 

  • BROWN, M. C. (1984) Sprouting of motor nerves in adult muscles: A recapitulation of ontogeny. Trends Neuroscience 7, 1–14.

    Google Scholar 

  • BURGESS, R. W., NGUYEN, Q. T., SON, Y. J., LICHTMAN, J. W. & SANES, J. R. (1999) Alternatively spliced isoforms of nerve-and muscle-derived agrin: Their roles at the neuromuscular junction. Neuron 23, 3–44.

    PubMed  Google Scholar 

  • BURKE, R. E. (1994) Physiology of motor units. In Myology (edited by ENGEL, A. G. & FRANZINIARMSTRONG, C.) pp. 46–484. New York: McGraw-Hill.

    Google Scholar 

  • CARONI, P. & BECKER, M. (1992) The downregulation of growth-associated proteins in motoneurons at the onset of synapse elimination is controlled by muscle activity and IGF1. Journal of Neuroscience 12, 384–3861.

    PubMed  Google Scholar 

  • CARONI, P. (1997a) Overexpression of growth-associated proteins in the neurons of adult transgenic mice. Journal of Neuroscience Methods 71, –9.

    PubMed  Google Scholar 

  • CARONI, P. (1997b) Intrinsic neuronal determinants that promote axonal sprouting and elongation. Bioessays 19, 76–775.

    PubMed  Google Scholar 

  • CARONI, P., AIGNER, L. & SCHNEIDER, C. (1997) Intrinsic neuronal determinants locally regulate extrasynaptic and synaptic growth at the adult neuromuscular junction. Journal of Cell Biology 136, 67–692.

    PubMed  Google Scholar 

  • CHIU, A. Y., ZHAI, P., DAL CANTO, M. C., PETERS, T. M., KWON, Y. W., PRATTIS, S. M. & GURNEY, M. E. (1995) Age-dependent penetrance of disease in a transgenic mouse model of familial amyotrophic lateral sclerosis. Molecular Cellular Neuroscience 6, 34–362.

    Google Scholar 

  • DAVIS, G. W. & GOODMAN, C. S. (1998) Synapse-specific control of synaptic efficacy at the terminals of a single neuron. Nature 392, 8–86.

    PubMed  Google Scholar 

  • DAVIS, G.W. (2000) The making of a synapse: Targetderived signals and presynaptic differentiation. Neuron 26, 55–554.

    PubMed  Google Scholar 

  • DE PAIVA, A., MEUNIER, F. A., MOLGO, J., AOKI, K. R. & DOLLY, J. O. (1999) Functional repair of motor endplates after botulinum neurotoxin type A poisoning: Biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Precedures of the National Academy of Sciences USA 96, 320–3205.

    Google Scholar 

  • DEPAOLA, V., ARBER, S. & CARONI, P. (2003) Dynamic equilibrium of presynaptic terminal numbers regulated by AMPA-receptor activation in mature hippocampal networks. Nature Neuroscience 6, 49–500.

    PubMed  Google Scholar 

  • FITZSIMONDS, R. M. & POO, M. M. (1998) Retrograde signaling in the development and modification of synapses. Physiology Reviews 78, 14–170.

    Google Scholar 

  • FREY, D., SCHNEIDER, C., XU, L., BORG, J., SPOOREN, W. & CARONI, P. (2000a) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. Journal of Neuroscience 20, 253–2542.

    PubMed  Google Scholar 

  • FREY, D., LAUX, T., XU, L., SCHNEIDER, C. & CARONI, P. (2000b) Shared and unique roles of CAP23 and GAP43 in actin regulation, neurite outgrowth, and anatomical plasticity. Journal of Cell Biology 149, 144–1454.

    PubMed  Google Scholar 

  • FRUGIER, T., NICOLE, S., CIFUENTES-DIAZ, C. & MELKI, J. (2002) The molecular bases of spinal muscular atrophy. Current Opinion in Genetics and Development 12, 29–298.

    PubMed  Google Scholar 

  • GAUTAM, M., NOAKES, P. G., MUDD, J., NICHOL, M., CHU, G. C., SANES, J. R. & MERLIE, J. P. (1995) Failure of postsynaptic specialization to develop at neuromuscular junctions of rapsyn-deficient mice. Nature 377, 23–236.

    PubMed  Google Scholar 

  • GAUTAM, M., NOAKES, P. G., M OSCOSO, L., RUPP, F., SCHELLER, R. H., MERLIE, J. P. & SANES, J. R. (1996) Defective neuromuscular synaptogenesis in agrindeficient mutant mice. Cell 85, 52–535.

    PubMed  Google Scholar 

  • GOLDBERG, J. L., KLASSEN, M. P., HUA, Y. & BARRES, B. A. (2002a) Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 186–1864.

    PubMed  Google Scholar 

  • GOLDBERG, J. L., ESPINOSA, J. S., XU, Y., DAVIDSON, N., KOVACS, G. T. & BARRES, B. A. (2002b) Retinal ganglion cells do not extend axons by default: Promotion by neurotrophic signaling and electrical activity. Neuron 33, 68–702.

    PubMed  Google Scholar 

  • GONZALEZ, M., RUGGIERO, F. P., CHANG, Q., SHI, Y. J., RICH, M. M., KRANER, S. & BALICEGORDON, R. J. (1999) Disruption of Trkb-mediated signaling induces disassembly of postsynaptic receptor clustering at neuromuscular junctions. Neuron 24, 56– 583.

    PubMed  Google Scholar 

  • GURNEY, M. E., PU, H., CHIU, A. Y., DAL CANTO, M. C., POLCHOW, C. Y., ALEXANDER, D. D., CALIENDO, J., HENTATI, A., KWON, Y. W., DENG, H. X., CHEN, W., ZHAI, P., SUFIT, R. L. & SIDDIQUE, T. (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264, 177–1775.

    PubMed  Google Scholar 

  • HEATHCOTE, R. D., EKMAN, J. M., CAMPBELL, K. P. & GODFREY, E. W. (2000) Dystroglycan overexpression in vivo alters acetylcholine receptor aggregation at the neuromuscular junction. Developmental Biology 227, 59–605.

    PubMed  Google Scholar 

  • HERRERA, A. A., QIANG, H. & KO, C. P. (2000) The role of perisynaptic Schwann cells in development of neuromuscular junctions in the frog (Xenopus laevis). Journal of Neurobiology 45, 23–254.

    PubMed  Google Scholar 

  • JACOBSON, C., CÔTÉ, P. D., ROSSI, S. G., ROTUNDO, R. L. & CARBONETTO, S. (2001) The dystroglycan complex is necessary for stabilization of acetylcholine receptor clusters at the neuromuscular junctions and formation of the synaptic basement membrane. Journal of Cell Biology 152, 43–450.

    PubMed  Google Scholar 

  • JONES C. L. (1979) The morphogenesis of the thigh of the mouse with special reference to tetrapod muscle homologies. Journal of Morphology 162, 27–309.

    PubMed  Google Scholar 

  • LIN, W., BURGESS, R. W., GOMINGUEZ, B., PFAFF, S. L., SANES, J. R. & LEE, K. F. (2001) Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 105–1064.

    PubMed  Google Scholar 

  • LIVET, J., SIGRIST, M., STROEBEL, S., DEPAOLA., V., PRICE, S. R., HENDERSON, C. E., JESSELL, T. M. & ARBER, S. (2002) ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 35, 87–892.

    PubMed  Google Scholar 

  • LOVE, F. M. & THOMPSON, W. J. (1999) Glial cells promote muscle reinnervation by responding to activity-dependent postsynaptic signals. J. Neurosci. 19, 1039–10396.

    PubMed  Google Scholar 

  • MARANGI, P. A., WIELAND, S. T. & FUHRER, C. (2002) Laminin-1 redistributes postsynaptic proteins and requires rapsyn, tyrosine phosphorylation, and Src and Fyn to stably cluster acetylcholine receptors. Journal of Cell Biology 157, 88–895.

    PubMed  Google Scholar 

  • MCKINNEY, R. A., CAPOGNA, M., DURR, R., GAEHWILER, B. H. & THOMPSON, S. M. (1999) Miniature synaptic events maintain dendritic spines via AMPA receptor activation. Nature Neuroscience 2, 4–49.

    PubMed  Google Scholar 

  • MISGELD, T., BURGESS, R. W., L EWIS, R. M., CUNNINGHAM, J. M., LICHTMAN, J. W. & SANES, J. R. (2002) Roles of neurotransmitter in synapse formation: Development of neuromuscular junctions lacking choline acetyltransferase. Neuron 36, 63–648.

    PubMed  Google Scholar 

  • O'ROURKE, N. A., CLINE, H. T. & FRASER, S. E. (1994) Rapid remodeling of retinal arbors in the tectum with and without blockade of synaptic transmission. Neuron 12, 92–934.

    PubMed  Google Scholar 

  • PINTER, M. J., WALDECK, R. F., WALLACE, N. & CORK, L. C. (1995) Motor unit behavior in canine motor neuron disease. Journal of Neuroscience 15, 344–3457.

    PubMed  Google Scholar 

  • PINTER, M. J., WALDECK, R. F., COPE, T. C. & CORK, L. C. (1997) Effects of 4-aminopyridine on muscle and motor unit force in canine motor neuron disease. Journal of Neuroscience 17, 450–4507.

    PubMed  Google Scholar 

  • PUN, S., SIGRIST, M., SANTOS, A. F., RUEGG, M. A., SANES, J. R., JESSELL, T. M., ARBER, S. & CARONI, P. (2002) An intrinsic distinction in neuromuscular junction assembly and maintenance in different skeletal muscles. Neuron 34, 35–370.

    PubMed  Google Scholar 

  • RAFF, M. C., WHITMORE, A. V. & FINN, J. T. (2002) Axonal self-destruction and neurodegeneration. Science 296, 86–871.

    PubMed  Google Scholar 

  • REYNOLDS, M. L. & WOOLF, C. J. (1992) Terminal Schwann cells elaborate extensive processes following denervation of the motor endplate. Journal of Neurocytology 21, 5–66.

    PubMed  Google Scholar 

  • RICH, M. M., WANG, X., COPE, T. C. & PINTER, M. J. (2002a) Reduced neuromuscular quantal content with normal synaptic release time course and depression in canine motor neuron disease. Journal of Neurophysiology 88, 330–3314.

    PubMed  Google Scholar 

  • RICH, M. M., WALDECK, R. F., CORK, L. C., BALICEGORDON, R. J., FYFFE, R. E., WANG, X., COPE, T. C. & PINTER, M. J. (2002b) Reduced endplate currents underlie motor unit dysfunction in canine motor neuron disease. Journal of Neurophysiology 88, 329–32304.

    PubMed  Google Scholar 

  • ROBITAILLE, R. (1998) Modulation of synaptic efficacy and synaptic depression by glial cells at the frog neuromuscular junction. Neuron 21, 84–855.

    PubMed  Google Scholar 

  • SAGOT, Y., DUBOIS-DAUPHIN, M., TAN, S. A., DE BILBAO, F., AEBISCHER, P., MARTINOU, J. C. & KATO, A. C. (1995) Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease. Journal of Neuroscience 15, 772–7733.

    PubMed  Google Scholar 

  • SAGOT, Y., TAN, S. A., HAMMANG, J. P., AEBISCHER, P. & KATO, A. C. (1996) GDNF slows loss of motoneurons but not axonal degeneration or premature death ofpmn/pmnmice. Journal of Neuroscience 16, 233– 2341.

    PubMed  Google Scholar 

  • SAGOT, Y., ROSSE, T., VEJSADA, R., PERRELET, D. & KATO, A. C. (1998) Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease. Journal of Neuroscience 18, 113–1141.

    PubMed  Google Scholar 

  • SANDROCK, A. W. JR., DRYER, S. E., ROSEN, K. M., GOZANI, S. N., KRAMER, R., THEILL, L. E. & FISCHBACH, G. D. (1997) Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo. Science 276, 59–603.

    PubMed  Google Scholar 

  • SANES, J. R. & LICHTMAN, J. W. (1999) Development of the vertebrate neuromuscular junction. Annual Reviews of Neuroscience 22, 38–442.

    Google Scholar 

  • SANES, J. R. & LICHTMAN, J. W. (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nature Reviews Neuroscience 2, 79–805.

    PubMed  Google Scholar 

  • SIEGEL, S. G., PATTON, B. & ENGLISH, A. W. (2000) Ciliary neurotrophic factor is required for motoneuron sprouting. Experimental Neurology 166, 20–212.

    PubMed  Google Scholar 

  • SKENE, J. H. P. (1989) Axonal growth-associated proteins. Annual Reviews Neuroscience 12, 12–156.

    Google Scholar 

  • SKORPEN, J., LAFOND-BENESTAD, S. & LOMO, T. (1999) Regulation of the size and distribution of ectopic neuromuscular junctions in adult skeletal muscle by nerve-derived trophic factor and electrical muscle activity. Molecular Cellular Neuroscience 13, 19–206.

    Google Scholar 

  • SON, Y. J. & THOMPSON, W. J. (1995) Nerve sprouting in muscle is induced and guided by processes extended by Schwann cells. Neuron 14, 13–141.

    PubMed  Google Scholar 

  • TAM, S. L., ARCHIBALD, V., TYREMAN, N. & GORDON, T. (2001) Increased neuromuscular activity reduces sprouting in partially denervated muscles. Journal of Neuroscience 21, 65–667.

    PubMed  Google Scholar 

  • VERHAGE, M., MAIA, A. S., PLOMP, J. J., BRUSSARD, A. B., HEEROMA, J. H., VERMEER, H., TOONEN, R. F., HAMMER, R. E., VAN DEN BERG, T. K., MISSLER, M. et al. (2000) Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science 287, 86–869.

    PubMed  Google Scholar 

  • WESTON, C., YEE, B, HOD, E. & PRIVES, J. (2000) Agrininduced acetylcholine receptor clustering is mediated by the small guanosine triphosphatases Rac and Cdc42. Journal of Cell Biology 150, 20–212.

    PubMed  Google Scholar 

  • WIDMER, F. & CARONI, P. (1990) Identification, localization, and primary structure of CAP-23, a particle-bound cytosolic protein of early development. Journal of Cell Biology 111, 303–3047.

    PubMed  Google Scholar 

  • WOLDEYESUS, M. T., BRITSCH, S., RIETHMACHER, D., XU, L., SONNENBERG-RIETHMACHER, E., ABOU-REBYEH, F., HARVEY, R., CARONI, P. & BIRCHMEIER, C. (1999) Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development. Genes and Development 13, 253– 2548.

    PubMed  Google Scholar 

  • YANG, J. F., CAO, G., KOIRALA, S., REDDY, L. V. & KO, C. P. (2001a) Schwann cells express active agrin and enhance aggregation of acetylcholine receptors on muscle fibers. Journal of Neuroscience 21, 957–9584.

    PubMed  Google Scholar 

  • YANG, X., ARBER, S., WILLIAM, C., LI, L., TANABE, Y., JESSELL, T. M., BIRCHMEIER, C. & BURDEN, S. J. (2001b) Patterning of muscle acetylcholine receptor gene expression in the absence of motor innervation. Neuron 30, 39–410.

    PubMed  Google Scholar 

  • ZHEN, G. L., WANG, Q., ZHOU, J. Z., WANG, J., LUO, Z., LIU, M., HE, X., WYNSCHAW-BORIS, A., XIONG, W. C., LU, B. & MEI, L. (2002) Regulation of AChR clustering by dishevelled interacting with MuSK and PAK1. Neuron 35, 48–505.

    PubMed  Google Scholar 

  • ZITO, K. & SVOBODA, K. (2002) Activity-dependent synaptogenesis in the adult Mammalian cortex. Neuron 35, 101–1017.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Novartis Research Foundation, Friedrich Miescher Institut, Basel, Switzerland

    Alexandre Ferrão Santos & Pico Caroni

Authors
  1. Alexandre Ferrão Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pico Caroni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pico Caroni.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santos, A.F., Caroni, P. Assembly, plasticity and selective vulnerability to disease of mouse neuromuscular junctions. J Neurocytol 32, 849–862 (2003). https://doi.org/10.1023/B:NEUR.0000020628.36013.88

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NEUR.0000020628.36013.88

Keywords

Search

Navigation