Abstract
ABSTRACTOtotoxicity is known to cause permanent loss of vestibule function through degeneration of sensory hair cells (HCs). However, functional recovery has been reported during washout after chronic ototoxicity, although the mechanisms underlying this reversible dysfunction are unknown. Here, we study this question in rats chronically exposed to the ototoxic compound 3,3′-iminodipropionitrile (IDPN). Pronounced alterations in vestibular function appeared before significant loss of HCs or stereociliary coalescence became evident by ultrastructural analyses. This early dysfunction was fully reversible if the exposure was terminated promptly. In cristae and utricles, the distinct junctions formed between type I HCs (HCI) and calyx endings were completely dismantled at these early stages of reversible dysfunction, and completely rebuilt during washout. Immunohistochemical observations revealed loss and recovery of the junction proteins CASPR1 and tenascin-C and RT-PCR indicated that their loss was not due to decreased gene expression. KCNQ4 was mislocalized during intoxication and recovered control-like localization after washout. At early stages of the intoxication, the calyces could be classified as showing intact or lost junctions, indicating that calyceal junction dismantlement is triggered on a calyx-by-calyx basis. Chronic toxicity also altered the presence of ribeye, PSD-95 and GluA2 puncta in the calyces. These synaptic alterations varied between the two types of calyx endings (formed by calyx-only or dimorphic afferents) and some persisted at the end of the washout period. The present data reveal new forms of plasticity of the calyx endings in adult mammals, including a robust capacity for rebuilding the calyceal junction. These findings contribute to a better understanding of the phenomena involved in progressive vestibular dysfunction and its potential recovery during and after ototoxic exposure.
Highlights
Impaired function of the vestibular system causes vertigo, loss of balance and loss of gaze fixation during movement, often accompanied by dizziness and nausea
The authors observed that severe vestibular dysfunction appears before major damage to the hair cells (HCs) occurs, and that this early dysfunction is reversible if the exposure is halted promptly
This ultrastructural evidence was corroborated by immunohistochemical data demonstrating major reductions in the content of the junction proteins CASPR1 and tenascin-C and redistribution of the voltage-gated potassium channel KCNQ4 in the epithelia
Summary
Impaired function of the vestibular system causes vertigo, loss of balance and loss of gaze fixation during movement, often accompanied by dizziness and nausea. One cause of vestibular dysfunction is inner ear damage following exposure to ototoxic chemicals. These include therapeutic drugs, such as aminoglycoside. Avian and amphibian species, the sensory epithelium produces new HCs to replace lost ones, synapses are recovered and tissue repair results in functional recovery (reviewed by Rubel et al, 2013), the application of cisplatin may block regeneration (Slattery and Warchol, 2010). HC regeneration capacity persists to a limited extent in some mammalian species (Forge et al, 1993; Warchol et al, 1993), it does not provide significant functional recovery (Forge and Schacht, 2000; Groves, 2010; Rubel et al, 2013). Human data are very rare (Tsuji et al, 2000) and provide only limited information on major pathological alterations
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