Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

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Abstract

Sensory hair cells receive near constant stimulation by omnipresent auditory and vestibular stimuli. To detect and encode these stimuli, hair cells require steady ATP production, which can be accompanied by a buildup of mitochondrial byproducts called reactive oxygen species (ROS). ROS buildup is thought to sensitize hair cells to ototoxic insults, including the antibiotic neomycin. Work in neurons has shown that neurotransmission is a major driver of ATP production and ROS buildup. Therefore, we tested whether neurotransmission is a significant contributor to ROS buildup in hair cells. Using genetics and pharmacology, we disrupted two key aspects of neurotransmission in zebrafish hair cells: presynaptic calcium influx and the fusion of synaptic vesicles. We find that chronic block of neurotransmission enhances hair-cell survival when challenged with the ototoxin neomycin. This reduction in ototoxin susceptibility is accompanied by reduced mitochondrial activity, likely due to a reduced ATP demand. In addition, we show that mitochondrial oxidation and ROS buildup are reduced when neurotransmission is blocked. Mechanistically, we find that it is the synaptic vesicle cycle rather than presynaptic- or mitochondrial-calcium influx that contributes most significantly to this metabolic stress. Our results comprehensively indicate that, over time, neurotransmission causes ROS buildup that increases the susceptibility of hair cells to ototoxins.

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All summary data (Figures 1-7 and all supplements) generated or analyzed in this study are included in the Source Data files.

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Daria Lukasz

Section on Sensory Cell Development and Function, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8220-7712
Alisha Beirl

Section on Sensory Cell Development and Function, National Institutes of Health, Bethesda, United States

Competing interests
The authors declare that no competing interests exist.
Katie Kindt

Section on Sensory Cell Development and Function, National Institutes of Health, Bethesda, United States

For correspondence
katie.kindt@nih.gov

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1065-8215

Funding

National Institute on Deafness and Other Communication Disorders (1ZIADC000085-01)

Daria Lukasz
Alisha Beirl
Katie Kindt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Zebrafish work performed at the National Institutes of Health (NIH) was approved by the Animal Use Committee at the NIH under animal study protocol #1362-13.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.