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  1. Evaluation Summary:

    Hair cell activity has been postulated to underlie their vulnerability to environmental insult including toxin exposure. Previous work has been confounded by the fact that reducing mechanotransduction also reduces entry of toxic chemicals. Here Lukasz and colleagues test these ideas by examining the vulnerability of zebrafish mutants with impaired synaptic activity, thought to be a major driver of neuronal metabolic load.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    This is an interesting study by Lukasz et al as they attempt to link chronic neurotransmission and metabolic stress in sensory hair cells in the zebrafish lateral line system. Previous work has shown that neurotransmission is major driver of ATP production and ROS buildup in neurons and is hypothesized in this study to affect superimposed regulate oxidative stress in hair cells, such as those imposed by ototoxins such as aminoglycosides.

    Strengths: the authors used 2 genetically modified zebrafish lines that disrupted presynaptic calcium influx, or the fusion of synaptic vesicles, respectively, and reported that hair cell survival was modestly enhanced after ototoxic damage which was accompanied by reduced mitochondrial activity based on live cell imaging. Pharmacologic experiments also nicely confirmed these findings. Based on comparative experiments, synaptic vesicle fusion contributed more significantly to metabolic stress.

    Weakness. Interestingly, age of hair cells also displayed differential neurotransmission and sensitivity of ototoxicity, which, unfortunately, complicates the interpretation of the above findings which were not analyzed based on cell age.

    Overall this is a well written manuscript and easy to follow, describing a topic that is highly significant, however, the data fall short of supporting all the conclusions made.

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  3. Reviewer #2 (Public Review):

    In this manuscript Lukasz et al., investigate the role of neurotransmission in hair cell toxicity. They first show that chronic inhibition of both presynaptic calcium influx and exocytosis either using genetic mutants or long-term treatment with drugs leads to protection from multiple forms of aminoglycoside-induced hair cell death. They then go on to investigate potential mechanisms for this protection showing that while drug uptake and clearance are normal in these mutants there is reduced mitochondria activity and oxidation, which has previously been linked to reduced hair cell death. They also show that as hair cells age they become synaptically silent suggesting a potential homeostatic mechanism for avoiding the oxidation being caused by synaptic activity.

    Strengths:

    The researchers clearly show disrupting synaptic activity can protect hair cells from ototoxic insult. The use of both mutant lines and drugs to eliminate synaptic activity both strengthens their conclusions and in the case of the drugs allowed them to work out the timing of this effect showing that chronic but not acute synaptic activity blockage is important. Additionally, by using a mutant and drug that disrupted endocytosis while leaving presynaptic calcium and mitochondrial calcium undisrupted they were able to specifically highlight the role of the synaptic vesicle cycle and not just calcium influx.

    Many things protect hair cells from ototoxic insult by affecting hair cell mechanotransduction activity and thus toxin uptake. The authors nicely address this confound by looking at mechanotransduction activity in their mutants, as well as drug uptake and clearance and show these look grossly normal.

    The authors addressed the unexpected results of seeing more hair cell death in synaptically silent as compared to active hair cells in a single neuromast by investigating the age of the active vs inactive hair cells and come up with an additional finding that active hair cells tend to be younger. This along with the investigation of mitochondria activity and oxidation when synaptic activity is disrupted broadens the relevance of the paper behind just ototoxic hair cell death.

    Weaknesses:

    The majority of measures of mitochondria oxidation and activity use the fluorescence levels of a single colored dye. If for some reason these dyes were not able to get into the hair cells or mitochondria of the mutant animals this would confound their results. It is true that the authors don't see significant defects in Neomycin uptake in their mutants, but for the otofb mutant it seems a decrease may be emerging with time and the mitochondrial dyes used longer treatment periods. One thing supporting the validity of the dye data is that the TMRE data shows the same patterns as the MitoTimer data which is a genetically encoded indicator.

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