A mouse model of the slow channel myasthenic syndrome: Neuromuscular physiology and effects of ephedrine treatment

R. G. Webster, Judith Cossins, D. Lashley, Susan Maxwell, W. W. Liu, J. R. Wickens, P. Martinez-Martinez, M. de Baets, David Beeson*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Web of Science)

Abstract

In the slow channel congenital myasthenic syndrome mutations in genes encoding the muscle acetylcholine receptor give rise to prolonged ion channel activations. The resulting cation overload in the postsynaptic region leads to damage of synaptic structures, impaired neuromuscular transmission and fatigable muscle weakness. Previously we identified and characterised in detail the properties of the slow channel syndrome mutation epsilon L221F. Here, using this mutation, we generate a transgenic mouse model for the slow channel syndrome that expresses mutant human epsilon-subunits harbouring an EGFP tag within the M3-M4 cytoplasmic region, driven by a similar to 1500 bp region of the CHRNB promoter. Fluorescent mutant acetylcholine receptors are assembled, cluster at the motor endplates and give rise to a disease model that mirrors the human condition. Mice demonstrate mild fatigable muscle weakness, prolonged endplate and miniature endplate potentials, and variable degeneration of the postsynaptic membrane. We use our model to investigate ephedrine as a potential treatment. Mice were assessed before and after six weeks on oral ephedrine (serum ephedrine concentration 89 +/- 3 ng/ml) using an inverted screen test and in vivo electromyography. Treated mice demonstrated modest benefit for screen hang time, and in measures of compound muscle action potentials and mean jitter that did not reach statistical significance. Ephedrine and salbutamol show clear benefit when used in the treatment of DOK7 or COLQ congenital myasthenic syndromes. Our results highlight only a modest potential benefit of these beta 2-adrenergic receptor agonists for the treatment of the slow channel syndrome.
Original languageEnglish
Pages (from-to)286-298
JournalExperimental Neurology
Volume248
DOIs
Publication statusPublished - Oct 2013

Keywords

  • Neuromuscular junction
  • Slow channel syndrome
  • Congenital myasthenia
  • Ephedrine
  • Electromyography
  • Mouse model
  • Fluorescent endplates
  • Acetylcholine receptor

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