PUBLICATION
Fatigue in Rapsyn-Deficient Zebrafish Reflects Defective Transmitter Release
- Authors
- Wen, H., Hubbard, J.M., Wang, W.C., Brehm, P.
- ID
- ZDB-PUB-161101-4
- Date
- 2016
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 36: 10870-10882 (Journal)
- Registered Authors
- Keywords
- myasthenic syndrome, neuromuscular, synaptic depression, synaptic plasticity, variance analysis, zebrafish
- MeSH Terms
-
- Animals
- Exocytosis/genetics
- Exocytosis/physiology
- Fatigue/genetics*
- Fatigue/metabolism*
- Female
- Male
- Motor Neurons
- Muscle Contraction/physiology
- Muscle Proteins/deficiency
- Muscle Proteins/genetics*
- Mutation/genetics
- Neurotransmitter Agents/metabolism*
- Patch-Clamp Techniques
- Synaptic Transmission/genetics
- Synaptic Transmission/physiology
- Zebrafish/physiology*
- PubMed
- 27798141 Full text @ J. Neurosci.
Citation
Wen, H., Hubbard, J.M., Wang, W.C., Brehm, P. (2016) Fatigue in Rapsyn-Deficient Zebrafish Reflects Defective Transmitter Release. The Journal of neuroscience : the official journal of the Society for Neuroscience. 36:10870-10882.
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.
Significance statement Use-dependent fatigue accompanies many neuromuscular myasthenic syndromes, including muscle rapsyn deficiency. Here, using a rapsyn-deficient line of zebrafish, we performed paired motor neuron target muscle patch-clamp recordings to investigate the mechanisms causal to this phenomenon. Our findings indicate that the reduced postsynaptic receptor density resulting from defective rapsyn contributes to weakness, but is not solely responsible for use-dependent fatigue. Instead, we find unexpected involvement of altered transmitter release from the motor neuron. Specifically, slowed reloading of vesicle release sites leads to augmented synaptic depression during repeated action potentials. Even at moderate stimulus frequencies, the depression levels for evoked synaptic responses fall below the threshold for the generation of muscle action potentials. The associated contraction failures are manifest as use-dependent fatigue.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping