Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation

Abstract

Accumulation of excess glutamate plays a central role in eliciting the pathological events that follow intensely loud noise exposures and ischemia-reperfusion injury. Glutamate excitotoxicity has been characterized in cochlear nerve terminals, but much less is known about whether excess glutamate signaling also contributes to pathological changes in sensory hair cells. I therefore examined whether glutamate excitotoxicity damages hair cells in zebrafish larvae exposed to drugs that mimic excitotoxic trauma. Exposure to ionotropic glutamate receptor (iGluR) agonists, kainic acid (KA) or N-methyl-D-aspartate (NMDA), contributed to significant, progressive hair cell loss in zebrafish lateral-line organs. To examine whether hair-cell loss was a secondary effect of excitotoxic damage to innervating neurons, I exposed neurog1a morphants—fish whose hair-cell organs are devoid of afferent and efferent innervation—to KA or NMDA. Significant, dose-dependent hair-cell loss occurred in neurog1a morphants exposed to either agonist, and the loss was comparable to wild-type siblings. A survey of iGluR gene expression revealed AMPA-, Kainate-, and NMDA-type subunits are expressed in zebrafish hair cells. Finally, hair cells exposed to KA or NMDA appear to undergo apoptotic cell death. Cumulatively, these data reveal that excess glutamate signaling through iGluRs induces hair-cell death independent of damage to postsynaptic terminals.

Identification of ion-channel modulators that protect against aminoglycoside-induced hair cell death

“…While it has been unclear whether hair cell death is due to a direct effect on hair cells or due to an indirect effect via receptors present on the afferent fibers innervating the hair cells (44), a recent study in zebrafish has shown that excess glutamate signaling through ionotropic glutamate receptors induces hair cell death irrespective of the presence or absence of nerve fibers (45). Compounds 13142 and 13222 may therefore prevent aminoglycoside-induced hair cell death by blocking Ca 2+ entry into hair cells via NMDA receptors (41,42,46).…”

Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse

“…Long-term studies of the mammalian cochlea have recently revealed that even a single incidence of noise overexposure can produce cochlear synaptopathy and neurodegeneration, exacerbating age-related hearing loss (Kujawa and Liberman, 2009;Lin et al, 2011). A major advance toward understanding this synaptopathy is to determine the cause of the initial excitotoxic insult.…”

L-type voltage-gated calcium channel agonists improve hearing loss and modify ribbon synapse morphology in the zebrafish model of Usher Syndrome Type 1

“…A potential explanation as to why we are observing adverse 547 effects in wildtype fish upon incubation with (±)-Bay K 8644 in not only the acoustic startle but 548 also in the distribution of CTBP2 puncta and the absolute smooth orientation is that excessive 549 cytosolic calcium (altering calcium homeostasis) in the hair cell can be detrimental (Esterberg et 550 al., 2013). Another explanation could be that the elevated cytosolic calcium in the wildtype hair 551 cells due to (±)-Bay K 8644 could be causing excessive activation of the glutamate receptors 552 that has been linked to apoptotic hair-cell death (Sheets, 2017). We may be observing this 553 affect across various assessments with only (±)-Bay K 8644, in the wildtype animals because it 554 is the more potent drug.…”