Mechanical overstimulation causes acute injury and synapse loss followed by fast recovery in lateral-line neuromasts of larval zebrafish

  1. Melanie Holmgren
  2. Michael E Ravicz
  3. Kenneth E Hancock
  4. Olga Strelkova
  5. Dorina Kallogjeri
  6. Artur A Indzhykulian
  7. Mark E Warchol
  8. Lavinia Sheets  Is a corresponding author
  1. Washington University School of Medicine in St Louis, United States
  2. Massachusetts Eye and Ear, United States
  3. Washington University School of Medicine in St. Louis, United States
  4. Harvard Medical School, United States
  5. Washington University School of Medicine, United States

Abstract

Excess noise damages sensory hair cells, resulting in loss of synaptic connections with auditory nerves and, in some cases, hair-cell death. The cellular mechanisms underlying mechanically induced hair-cell damage and subsequent repair are not completely understood. Hair cells in neuromasts of larval zebrafish are structurally and functionally comparable to mammalian hair cells but undergo robust regeneration following ototoxic damage. We therefore developed a model for mechanically induced hair-cell damage in this highly tractable system. Free swimming larvae exposed to strong water wave stimulus for 2 hours displayed mechanical injury to neuromasts, including afferent neurite retraction, damaged hair bundles, and reduced mechanotransduction. Synapse loss was observed in apparently intact exposed neuromasts, and this loss was exacerbated by inhibiting glutamate uptake. Mechanical damage also elicited an inflammatory response and macrophage recruitment. Remarkably, neuromast hair-cell morphology and mechanotransduction recovered within hours following exposure, suggesting severely damaged neuromasts undergo repair. Our results indicate functional changes and synapse loss in mechanically damaged lateral-line neuromasts that share key features of damage observed in noise-exposed mammalian ear. Yet, unlike the mammalian ear, mechanical damage to neuromasts is rapidly reversible.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 2, 3, 4 , and 7.

Article and author information

Author details

  1. Melanie Holmgren

    Otolaryngology-Head & Neck Surgery, Washington University School of Medicine in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Michael E Ravicz

    Eaton Peabody Laboratory, Massachusetts Eye and Ear, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9978-3444
  3. Kenneth E Hancock

    Eaton Peabody Laboratory, Massachusetts Eye and Ear, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Olga Strelkova

    Eaton Peabody Laboratory, Massachusetts Eye and Ear, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Dorina Kallogjeri

    Washington University School of Medicine in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Artur A Indzhykulian

    Department of Neurobiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Mark E Warchol

    Departments of Otolaryngology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lavinia Sheets

    Department of Otolaryngology, Washington University School of Medicine in St Louis, St Louis, United States
    For correspondence
    sheetsl@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5231-2450

Funding

National Institute on Deafness and Other Communication Disorders (R01DC016066)

  • Lavinia Sheets

National Institute on Deafness and Other Communication Disorders (R01DC017166)

  • Artur A Indzhykulian

National Institute on Deafness and Other Communication Disorders (R01DC006283)

  • Mark E Warchol

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

Ethics

Animal experimentation: This study was performed with the approval of the Institutional Animal Care and Use Committee of Washington University School of Medicine in St. Louis (protocol no. 20-0158) and in accordance with NIH guidelines for use of zebrafish.

Copyright

© 2021, Holmgren et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,222
    views
  • 182
    downloads
  • 13
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Melanie Holmgren
  2. Michael E Ravicz
  3. Kenneth E Hancock
  4. Olga Strelkova
  5. Dorina Kallogjeri
  6. Artur A Indzhykulian
  7. Mark E Warchol
  8. Lavinia Sheets
(2021)
Mechanical overstimulation causes acute injury and synapse loss followed by fast recovery in lateral-line neuromasts of larval zebrafish
eLife 10:e69264.
https://doi.org/10.7554/eLife.69264

Share this article

https://doi.org/10.7554/eLife.69264

Further reading

    1. Neuroscience
    Franziska Auer, Katherine Nardone ... David Schoppik
    Research Article

    Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.

    1. Neuroscience
    Gáspár Oláh, Rajmund Lákovics ... Gábor Tamás
    Research Article

    Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.