title: 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.
authors.affiliation: Eaton-Peabody Laboratory Massachusetts Eye and Ear Boston, MA 02114, USA.|Department of Otolaryngology Harvard Medical School Boston, MA 02115, USA.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Sheets
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D018698:Glutamic Acid / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000378:metabolism* / Q000502:physiology; D007608:Kainic Acid / Q000378:metabolism; D007814:Larva / Q000378:metabolism; D016202:N-Methylaspartate / Q000235:genetics; D009475:Neurons, Afferent / Q000378:metabolism; D009476:Neurons, Efferent / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D018092:Kainic Acid Receptors / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015027:Zebrafish / Q000378:metabolism
chemical_list: D018698:Glutamic Acid; D007608:Kainic Acid; D016202:N-Methylaspartate; D018091:Receptors, AMPA; D058468:Receptors, Ionotropic Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate