Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation.
Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation.
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离子型谷氨酸受体的过度激活会导致毛细胞凋亡，与传入和传出神经支配无关。
DOI：
10.1038/srep41102
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发表时间：
2017
影响因子：
4.6
通讯作者：
Sheets,Lavinia
中科院分区：
文献类型：
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作者：
Sheets,Lavinia
过量谷氨酸的积累在引发强噪声暴露和缺血再灌注损伤后的病理事件中起着核心作用。谷氨酸兴奋性毒性的特点是在耳蜗神经末梢，但很少有人知道过量的谷氨酸信号是否也有助于感觉毛细胞的病理变化。因此，我研究了谷氨酸兴奋性毒性是否会损害斑马鱼幼虫暴露于模拟兴奋性毒性创伤的药物中的毛细胞。暴露于离子型谷氨酸受体（iGluR）激动剂，红藻氨酸（KA）或N-甲基-D-天冬氨酸（NMDA），导致显着的，进行性的毛细胞损失在斑马鱼侧线器官。为了研究毛细胞损失是否是兴奋性毒性损伤神经支配的神经元的继发性影响，我exposedneurog 1 amorphants鱼的毛细胞器官是缺乏传入和传出神经支配KA或NMDA。显著的，剂量依赖性的毛细胞损失发生在暴露于任一激动剂的neurog 1amorphants中，这种损失与野生型同胞相当。对iGluR基因表达的调查显示，斑马鱼毛细胞中表达AMPA-、红藻氨酸盐-和NMDA-型亚基。最后，暴露于KA或NMDA的毛细胞似乎经历凋亡性细胞死亡。累积起来，这些数据表明，过量的谷氨酸信号通过iGluRs诱导毛细胞死亡的损伤突触后终端独立。
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 exposedneurog1amorphants—fish whose hair-cell organs are devoid of afferent and efferent innervation—to KA or NMDA. Significant, dose-dependent hair-cell loss occurred inneurog1amorphants 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.