Nuclear factor κB deficiency is associated with auditory nerve degeneration and increased noise-induced hearing loss
Nuclear factor κB deficiency is associated with auditory nerve degeneration and increased noise-induced hearing loss
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DOI：
10.1523/jneurosci.2488-05.2006
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发表时间：
2006-03-29
影响因子：
5.3
通讯作者：
Schmiedt, RA
中科院分区：
文献类型：
--
作者：
Lang, HN;Schulte, BA;Schmiedt, RA
听神经的螺旋神经节神经元（SGN）的变性随着年龄的增长和对声损伤的反应而发生。组织学观察表明，神经变性通常始于影响内毛细胞（IHC）下的传入树突的兴奋性毒性过程，然而，很少有人知道介导这种兴奋性毒性的细胞或分子事件的顺序。核因子κ B（NF κ B）是一种转录因子，参与调节多种细胞的炎症反应和凋亡。NF κ B还与细胞内钙调节相关，这是神经元兴奋性毒性的重要因素。在这里，我们提供的证据表明，NF κ B B可以发挥核心作用，在变性的SGN。缺乏NF κ B B p50亚单位的小鼠（p50（-/-）小鼠）表现出随年龄增长而加速的听力损失，这与IHC下传入树突中的兴奋性毒性样损伤加剧和SGN的加速损失高度相关。此外，如免疫染色强度所证明的，钙缓冲蛋白在p50（-/-）小鼠的SGN中显著升高。最后，基因敲除小鼠表现出对低水平噪音暴露的敏感性增加。p50（-/-）小鼠随着年龄的增长而加速的听力损失和神经退行性变发生在没有伴随的毛细胞损失和耳蜗内电位下降的情况下。这些结果表明NF-κ B B活性在保护初级听神经元免受兴奋性毒性损伤和年龄相关性变性中起重要作用。这种保护的一个可能机制是NF κ B B活性可能有助于维持SGN中的钙稳态。
Degeneration of the spiral ganglion neurons (SGNs) of the auditory nerve occurs with age and in response to acoustic injury. Histopathological observations suggest that the neural degeneration often begins with an excitotoxic process affecting the afferent dendrites under the inner hair cells (IHCs), however, little is known about the sequence of cellular or molecular events mediating this excitotoxicity. Nuclear factor kappa B(NF kappa B) is a transcription factor involved in regulating inflammatory responses and apoptosis in many cell types. NF kappa B is also associated with intracellular calcium regulation, an important factor in neuronal excitotoxicity. Here, we provide evidence that NF kappa B can play a central role in the degeneration of SGNs. Mice lacking the p50 subunit of NF kappa B (p50(-/-) mice) showed an accelerated hearing loss with age that was highly associated with an exacerbated excitotoxic-like damage in afferent dendrites under IHCs and an accelerated loss of SGNs. Also, as evidenced by immunostaining intensity, calcium-buffering proteins were significantly elevated in SGNs of the p50(-/-) mice. Finally, the knock-out mice exhibited an increased sensitivity to low-level noise exposure. The accelerated hearing loss and neural degeneration with age in the p50(-/-) mice occurred in the absence of concomitant hair cell loss and decline of the endocochlear potential. These results indicate that NF kappa B activity plays an important role in protecting the primary auditory neurons from excitotoxic damage and age-related degeneration. A possible mechanism underlying this protection is that the NF kappa B activity may help to maintain calcium homeostasis in SGNs.