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

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.

Functional development and regeneration of hair cells in the zebrafish lateral line

“…The application of ototoxic compounds, such as aminoglycosides, or noise‐induced damage (Holmgren et al . 2020), has been shown to cause the rapid loss of hair cells in the early‐larval neuromasts, which is followed by their regeneration from surrounding supporting cells within ∼48 hpt (e.g. Harris et al .…”

Putative COVID-19 therapies imatinib, lopinavir, ritonavir, and ivermectin cause hair cell damage: A targeted screen in the zebrafish lateral line

“…Hair cell damage was first assessed in wildtype * AB larvae. Prior to drug treatment, fish were incubated in DAPI (catalog # MBD0015, Sigma-Aldrich, St. Louis, MO, United States; diluted to 1 µg/ml in EM) for 10 min at 28 • C. In live larvae, DAPI specifically labels lateral line hair cells and the label is retained after euthanasia (Uribe et al, 2018;Coffin et al, 2021;Holmgren et al, 2021;Lee et al, 2022; also see Supplementary Figure 1). Fish were then rinsed twice in EM and incubated for 24 h with variable concentrations (0.01-50 µM) in one of the following drugs (obtained from Sigma-Aldrich unless specified): remdesivir (catalog # 7226, Bio-Techne, Minneapolis, MN, United States), lopinavir, ritonavir, imatinib (catalog # S1380, S1185, S2475, respectively; Selleckchem, Houston, TX, United States), dexamethasone, azithromycin, or ivermectin (catalog # D1756, PHR1088, I8898, respectively).…”

Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles

“…Fisher’s exact test). The disorganized kinocilia bundle was a reminiscence of the kinocilia morphology seen in neuromasts following mechanical injury ( Holmgren et al, 2021 ).…”