Mutation of Foxo3 Causes Adult Onset Auditory Neuropathy and Alters Cochlear Synapse Architecture in Mice
Mutation of Foxo3 Causes Adult Onset Auditory Neuropathy and Alters Cochlear Synapse Architecture in Mice
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DOI：
10.1523/jneurosci.2529-13.2013
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发表时间：
2013-11-20
影响因子：
5.3
通讯作者：
White, Patricia M.
中科院分区：
文献类型：
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作者：
Gilels, Felicia;Paquette, Stephen T.;White, Patricia M.
听觉神经病是一种听力损失的形式，其中耳蜗内毛细胞无法正确编码或将声学信息传输到大脑。很少有基因与这种疾病的成人发病形式有关。在这里，我们表明，缺乏转录因子Foxo 3的小鼠有成年发病听力损失的标志性特征的听神经病，即，听觉阈值升高结合正常的外毛细胞功能。使用组织学技术，我们证明Foxo 3依赖性听力损失不是由于耳蜗毛细胞或螺旋神经节神经元的损失，这两者通常都表达Foxo 3。此外，Foxo 3敲除（KO）内毛细胞不显示突触数量的减少。相反，我们发现内毛细胞及其周围有微妙的结构变化。共聚焦显微镜结合3D建模和定量分析显示，Foxo 3-KO小鼠的突触定位发生改变，Myo 7a免疫反应性降低。TEM显示明显的传入变性。引人注目的是，声刺激促进体内Foxo 3核定位，这意味着耳蜗活动和突触功能维持之间的联系。总之，这些研究结果支持了一个新的作用，典型的损伤反应因子Foxo 3有助于维持听觉突触传递。
Auditory neuropathy is a form of hearing loss in which cochlear inner hair cells fail to correctly encode or transmit acoustic information to the brain. Few genes have been implicated in the adult-onset form of this disease. Here we show that mice lacking the transcription factor Foxo3 have adult onset hearing loss with the hallmark characteristics of auditory neuropathy, namely, elevated auditory thresholds combined with normal outer hair cell function. Using histological techniques, we demonstrate that Foxo3-dependent hearing loss is not due to a loss of cochlear hair cells or spiral ganglion neurons, both of which normally express Foxo3. Moreover, Foxo3-knock-out ( KO) inner hair cells do not display reductions in numbers of synapses. Instead, we find that there are subtle structural changes in and surrounding inner hair cells. Confocal microscopy in conjunction with 3D modeling and quantitative analysis show that synaptic localization is altered in Foxo3-KO mice and Myo7a immunoreactivity is reduced. TEM demonstrates apparent afferent degeneration. Strikingly, acoustic stimulation promotes Foxo3 nuclear localization in vivo, implying a connection between cochlear activity and synaptic function maintenance. Together, these findings support a new role for the canonical damage response factor Foxo3 in contributing to the maintenance of auditory synaptic transmission.