Mechanisms of hypersensitivity to sound-induced cochlear damage

项目摘要 有关声环境的所有信息由内耳的传入纤维传递到中枢神经系统。 耳蜗神经。快速门控AMPA谷氨酸受体(AMPAR；GluA2、GluA3和GluA4亚基) 在内毛细胞(IHC)和传入纤维之间的成熟突触上介导突触传递 耳蜗神经(IHC突触)。然而，每种类型的AMPAR亚基对总体的贡献 耳蜗谷氨酸能受体的功能和传入传递/敏感性还知之甚少。 了解这一过程很重要，因为已经涉及到通过AMPAR的谷氨酸兴奋性毒性 在噪声、缺血和衰老引起的听力损失的发病机制中起重要作用。易感性的性别差异 听力损失会发生在人类身上。因此，我们开始研究AMPAR亚基对 在IHC突触的传递以及AMPAR亚单位是否存在性别差异 会导致声音引起的耳蜗损伤和听力损失。基于功能和超微结构 初步数据，我们现在假设GluA3AMPAR亚基在性行为中起着关键作用 听力损失的两面性易感性“。从机械上定义GluA3如何对结构和 IHC突触的分子组成以及对声音敏感的性别差异- 我们将使用功能(ABR、DPOAE)、 免疫细胞化学(共聚焦显微镜)、生化、qRT-PCR和超微结构方法检测 遵循假设。在目标1中，我们将确定GluA3是否促进了IHC中GluA2的丰度 突触。在目标2中，我们将确定IHC突触上的GluA3是否能保护小鼠免受声音诱导 耳蜗骨损伤。目标3，基于已发表的数据和我们的初步发现，我们提出了假设 在缺乏GluA3的情况下，卵巢激素促进了对声音诱导的耳蜗声敏感 而雄激素则具有保护作用。这些拟议的研究是第一次解决 AMPAR亚基组成的变化如何导致听力损失的性别差异是一个重要的问题。

Project Summary All information about the acoustic environment is carried from the inner ear to the CNS by the afferent fibers of the cochlear nerve. Rapidly gating AMPA glutamate receptors (AMPAR; GluA2, GluA3 and GluA4 subunits) mediate synaptic transmission at the mature synapse between the inner hair cells (IHC) and the afferent fibers of the cochlear nerve (IHC synapse). However, the contribution of each type of AMPAR subunit to overall glutamatergic receptor function and afferent transmission/sensitivity in the cochlea is poorly understood. Understanding this process is important because glutamate excitotoxicity through AMPAR has been implicated in the pathogenesis of hearing loss caused by noise, ischemia and aging. Sex differences in the vulnerability to hearing loss occur in humans. We therefore began investigating the contribution of AMPAR subunits to transmission at the IHC synapse and whether there are sex-specific differences in AMPAR subunits that contribute to sound-induced cochlear damage and hearing loss. Based on functional and ultrastructural preliminary data, we now hypothesize that “GluA3 AMPAR subunits have a critical role in the sexually dimorphic vulnerability to hearing loss”. To define mechanistically how GluA3 contributes to the structural and molecular components of IHC synapses and to sex differences that underlie the hypersensitivity to sound- induced cochlear damage, we will use a powerful combination of functional (ABRs, DPOAEs), immunocytochemical (confocal microscopy), biochemical, qRT-PCR, and ultrastructural approaches to test the following hypotheses. In Aim 1, we will determine whether GluA3 promotes the abundance of GluA2 at IHC synapses. In Aim 2, we will determine whether GluA3 at IHC synapses protects mice from sound-induced cochlear damage. Aim 3, based on published data and our preliminary findings, we propose the hypothesis that in the absence of GluA3, ovarian hormones facilitate the hypersensitivity to sound-induced cochlear damage, while androgens have protective effects. These proposed studies are the first to address the important question of how changes in AMPAR subunit composition lead to sex differences in hearing loss.