Chronic neurotransmission increases the susceptibility of lateral-line hair cells to ototoxic insults

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.

Noise-induced synaptopathy impacts the long and short sensory hair cells differently in the mammalian cochlea

“…In line with this notion, a recent physiology study from CBA mice has revealed noise-induced reduction in both low- and high spontaneous-rate auditory fibers (Suthakar and Liberman, 2021). Thus, these evidences argue for a more complex and IHC subtype-specific ribbon plasticity following the classic glutamate-mediated damage on postsynaptic terminals, presumably involving local metabolic stress induced by presynaptic- or mitochondrial-Ca 2+ influx as well as synaptic vesicle cycle, as recently showed in zebrafish lateral-line hair cells (Lukasz et al, 2022). More importantly, quantification by using a global modiolar-pillar gradient may mask the differences between IHCs in a staggered arrangement, and thereby several prevailing concepts of synaptopathy might not strictly hold true in the functionally more relevant middle cochlea regions.…”

“…Sustained neurotransmission at high rate is metabolic demanding for nerve cells. Recent work suggests that the ribbon function is a significant contributor to ATP consumption and reactive oxygen species (ROS) buildup in zebrafish lateral-line hair cells (Lukasz et al, 2022), implying a crucial role of presynaptic mitochondrial network in the maintenance of neurotransmission. In line with this notion, ototoxin susceptibility of hair cells is correlated with mitochondrial activity (Lukasz et al, 2022; Pickett et al, 2018).…”

“…Recent work suggests that the ribbon function is a significant contributor to ATP consumption and reactive oxygen species (ROS) buildup in zebrafish lateral-line hair cells (Lukasz et al, 2022), implying a crucial role of presynaptic mitochondrial network in the maintenance of neurotransmission. In line with this notion, ototoxin susceptibility of hair cells is correlated with mitochondrial activity (Lukasz et al, 2022; Pickett et al, 2018). In the mammalian IHCs, an asymmetric mitochondrial distribution along the radial plane has been previously described (Bullen et al, 2015).…”

Activity regulates a cell type-specific mitochondrial phenotype in zebrafish lateral line hair cells

“…Not all HCs within zebrafish NMs are synaptically active, with active HCs tending to be younger cells on the NM periphery ( Zhang et al, 2018 ; Wong et al, 2019 ; Lukasz et al, 2022 ). This is interesting, considering that we find the largest mitochondrial networks in more mature HCs.…”

Hair cell toxicology: With the help of a little fish

“…Hair cell function is energy demanding, and the associated mitochondrial sustained activity to supply the required energy imposes a toll on hair cell susceptibility to aminoglycosides, altering mitochondrial turnover and repair ( Pickett et al, 2018 ). One cellular process that is responsible for energy demand is synaptic transmission between hair cells and their afferent neurons, as genetic or pharmacological blocking of synaptic transmission in hair cells provides protection from aminoglycoside (both neomycin and gentamicin)-induced cell death, precisely by reducing mitochondrial oxidation and accumulation of ROS ( Lukasz et al, 2022 ).…”