Get access

Anti-disialosyl antibodies mediate selective neuronal or Schwann cell injury at mouse neuromuscular junctions

Authors

  • Susan K. Halstead,

    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    Search for more papers by this author
  • Ian Morrison,

    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    Search for more papers by this author
  • Graham M. O'Hanlon,

    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    Search for more papers by this author
  • Peter D. Humphreys,

    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    Search for more papers by this author
  • John A. Goodfellow,

    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    Search for more papers by this author
  • Jaap J. Plomp,

    1. Departments of Neurology, Leiden University Medical Centre, The Netherlands
    2. Department of Neurophysiology, Leiden University Medical Centre, The Netherlands
    Search for more papers by this author
  • Hugh J. Willison

    Corresponding author
    1. Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow, Scotland
    • Department of Neurology, Division of Clinical Neurosciences, University of Glasgow, Southern General Hospital, Glasgow G51 4TF, Scotland
    Search for more papers by this author

Abstract

The human paralytic neuropathy, Miller Fisher syndrome (MFS) is associated with autoantibodies specific for disialosyl epitopes on gangliosides GQ1b, GT1a, and GD3. Since these gangliosides are enriched in synaptic membranes, anti-ganglioside antibodies may target neuromuscular junctions (NMJs), thereby contributing to disease symptoms. We have shown previously that at murine NMJs, anti-disialosyl antibodies induce an α-latrotoxin-like effect, electrophysiologically characterized by transient massive increase of spontaneous neurotransmitter release followed by block of evoked release, resulting in paralysis of the muscle preparation. Morphologically, motor nerve terminal damage, as well as perisynaptic Schwann cell (pSC) death is observed. The relative contributions of neuronal and pSC injury to the paralytic effect and subsequent repair are unknown. In this study, we have examined the ability of subsets of anti-disialosyl antibodies to discriminate between the neuronal and glial elements of the NMJ and thereby induce either neuronal injury or pSC death. Most antibodies reactive with GD3 induced pSC death, whereas antibody reactivity with GT1a correlated with the extent of nerve terminal injury. Motor nerve terminal injury resulted in massive uncontrolled exocytosis with paralysis. However, pSC ablation induced no acute (within 1 h) electrophysiological or morphological changes to the underlying nerve terminal. These data suggest that at mammalian NMJs, acute pSC injury or ablation has no major deleterious influence on synapse function. Our studies provide evidence for highly selective targeting of mammalian NMJ membranes, based on ganglioside composition, that can be exploited for examining axonal–glial interactions both in disease states and in normal NMJ homeostasis. © 2005 Wiley-Liss, Inc.

Ancillary