PUBLICATION
Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults
- Authors
- Lukasz, D., Beirl, A., Kindt, K.
- ID
- ZDB-PUB-220902-4
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Beirl, Alisha, Kindt, Katie
- Keywords
- cell biology, neuroscience, zebrafish
- MeSH Terms
-
- Adenosine Triphosphate
- Animals
- Calcium*/metabolism
- Neomycin/toxicity
- Reactive Oxygen Species
- Synaptic Transmission
- Zebrafish*/physiology
- PubMed
- 36047587 Full text @ Elife
Citation
Lukasz, D., Beirl, A., Kindt, K. (2022) Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults. eLIFE. 11:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping