Otoferlin Depletion Results in Abnormal Synaptic Ribbons and Altered Intracellular Calcium Levels in Zebrafish

The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytosis, it is...

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Bibliographic Details
Published in:Scientific reports 2019-10, Vol.9 (1), p.14273-10, Article 14273
Main Authors: Manchanda, Aayushi, Chatterjee, Paroma, Bonventre, Josephine A., Haggard, Derik E., Kindt, Katie S., Tanguay, Robert L., Johnson, Colin P.
Format: Article
Language:English
Subjects:
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Animal models
Animals
Antibodies
Calcium
Calcium (intracellular)
Calcium - metabolism
Danio rerio
Deafness
Embryos
Endocytosis
Exocytosis
Gene Deletion
Gene expression
Hair
Hair cells
Hair Cells, Auditory - metabolism
Hair Cells, Auditory - pathology
Humanities and Social Sciences
Laboratory animals
Larvae
multidisciplinary
Mutation
Nogo protein
Parvalbumin
Protein turnover
Science
Science (multidisciplinary)
Synapses
Synapses - genetics
Synapses - metabolism
Synapses - pathology
Synaptic ribbons
Transcription
Transcriptome
Vestibular system
Zebrafish
Zebrafish - genetics
Zebrafish - metabolism
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Summary:The protein otoferlin plays an essential role at the sensory hair cell synapse. Mutations in otoferlin result in deafness and depending on the species, mild to strong vestibular deficits. While studies in mouse models suggest a role for otoferlin in synaptic vesicle exocytosis and endocytosis, it is unclear whether these functions are conserved across species. To address this question, we characterized the impact of otoferlin depletion in zebrafish larvae and found defects in synaptic vesicle recycling, abnormal synaptic ribbons, and higher resting calcium concentrations in hair cells. We also observed abnormal expression of the calcium binding hair cell genes s100s and parvalbumin, as well as the nogo related proteins rtn4rl2a and rtn4rl2b. Exogenous otoferlin partially restored expression of genes affected by endogenous otoferlin depletion. Our results suggest that in addition to vesicle recycling, depletion of otoferlin disrupts resting calcium levels, alters synaptic ribbon architecture, and perturbs transcription of hair cells specific genes during zebrafish development.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-019-50710-2