Abstract
The formation and function of synapses are tightly orchestrated by the precise timing of expression of specific molecules during development. In this study, we determined how manipulating the timing of expression of postsynaptic acetylcholine receptors (AChRs) impacts presynaptic release by establishing a genetically engineered zebrafish line in which we can freely control the timing of AChR expression in an AChR-less fish background. With the delayed induction of AChR expression after an extensive period of AChR-less development, paralyzed fish displayed a remarkable level of recovery, exhibiting a robust escape response following developmental delay. Despite their apparent behavioral rescue, synapse formation in these fish was significantly altered as a result of delayed AChR expression. Motor neuron innervation determined the sites for AChR clustering, a complete reversal of normal neuromuscular junction (NMJ) development where AChR clustering precedes innervation. Most importantly, among the three modes of presynaptic vesicle release, only the spontaneous release machinery was strongly suppressed in these fish, while evoked vesicle release remained relatively unaffected. Such a specific presynaptic change, which may constitute a part of the compensatory mechanism in response to the absence of postsynaptic AChRs, may underlie symptoms of neuromuscular diseases characterized by reduced AChRs, such as myasthenia gravis.
Highlights
The vertebrate neuromuscular junction (NMJ) is a cholinergic synapse formed between a motor nerve and skeletal muscle
This chemically inducible system was crossed into sofa potato, a paralyzed mutant zebrafish line lacking postsynaptic acetylcholine receptors (AChRs) in the NMJ5
Treatment with RU486 at ~10 hpf led to movement of rescue sop (Fig. 1a, middle) that were indistinguishable from their wild type siblings (Fig. 1a, top), until the induced protein degenerated and disappeared after 3 dpf
Summary
The vertebrate NMJ is a cholinergic synapse formed between a motor nerve and skeletal muscle. By allowing a sufficient time lag before inducing the expression of AChRs, we could observe the effect of AChR-less development on NMJ synaptic currents. We found that these synapses exhibited remarkable adaptability, which inevitably led to functional transmission. These rescued synapses manifested characteristics that were remarkably distinct from their normally developed counterparts, namely the lack of spontaneous vesicle releases.
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