Fatigue in rapsyn-deficient zebrafish reflects defective transmitter release

Hua Wen, Jeffrey Michael Hubbard, Wei Chun Wang, Paul Brehm

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Rapsyn-deficient myasthenic syndrome is characterized by a weakness in voluntary muscle contraction, a direct consequence of greatly reduced synaptic responses that result from poorly clustered acetylcholine receptors. As with other myasthenic syndromes, the general muscle weakness is also accompanied by use-dependent fatigue. Here, we used paired motor neuron target muscle patch-clamp recordings from a rapsyn-deficient mutant line of zebrafish to explore for the first time the mechanisms causal to fatigue. We find that synaptic responses in mutant fish can follow faithfully low-frequency stimuli despite the reduced amplitude. This is in part helped by a compensatory increase in the number of presynaptic release sites in the mutant fish. In response to high-frequency stimulation, both wild-type and mutant neuromuscular junctions depress to steady-state response levels, but the latter shows exaggerated depression. Analysis of the steady-state transmission revealed that vesicle reloading and release at individual release sites is significantly slower in mutant fish during high-frequency activities. Therefore, reductions in postsynaptic receptor density and compromised presynaptic release collectively serve to reduce synaptic strength to levels that fall below the threshold for muscle action potential generation, thus accounting for use-dependent fatigue. Our findings raise the possibility that defects in motor neuron function may also be at play in other myasthenic syndromes that have been mapped to mutations in muscle-specific proteins.

Original languageEnglish (US)
Pages (from-to)10870-10882
Number of pages13
JournalJournal of Neuroscience
Volume36
Issue number42
DOIs
StatePublished - Oct 19 2016

Keywords

  • Myasthenic syndrome
  • Neuromuscular
  • Synaptic depression
  • Synaptic plasticity
  • Variance analysis
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience(all)

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