ATP-purinergic mechanisms underlying noise-induced cochlear synaptopathy and hearing loss

摘要 该项目的长期目标是研究噪声诱导的耳蜗病的潜在机制。 突触和隐匿性听力损失。噪音是听力损失的常见危险因素。最新研究 已经证明，即使是一次过度暴露的噪音也会导致短暂的听力损失， 即时间阈值漂移(TTS)，暴露在噪声中的动物可能没有毛细胞丢失，但有 广泛性螺旋神经节神经元(SG)和突触变性。特别是自发性低 (LSR)听神经及其与内毛细胞的突触连接优先丢失。这个 暴露在噪声中的动物和人类表现出正常的听力阈值和灵敏度(即， 隐性听力损失)，但最终会表现出其他听力障碍和听力 损失。目前，这种耳蜗性突触的潜在机制仍不清楚。 噪声刺激毛细胞和神经元过度激活，增加K+外流，导致 增加胞外K+浓度。众所周知，细胞外高K+可以诱导 毒性导致损伤和中风后大脑中的第二个细胞死亡。我们假设 噪声暴露后高、过多的细胞外K+也可引起SG突触和神经元 耳蜗骨的退化。我们先前在耳蜗处发现了ATP嘌呤能的P2X受体 需要下沉K+才能重新进入细胞。最近的一项研究还表明，P2X2 受体是TTS发育所必需的。此外，我们还发现，P2X2突变可以 增加对噪音的敏感性，并导致听力损失。这些研究表明，P2X受体 可能在噪声诱导的耳蜗性突触和隐性听力损失中起关键作用。在这 项目中，我们将首先测试细胞外高K+是否会导致SG突触和神经元 变性(特异性靶点1，SA1)。然后，我们将鉴定和表征P2X受体的表达 在SG神经元，包括LSR和HSR(高自发性)纤维突触终末，并测试 P2X受体是否能介导SG神经元的K+下沉。在SA3中，我们将测试 P2X受体缺乏可诱发和加重耳蜗性突触病变和听力损失 在噪声暴露和高K+挑战之后。这些研究的完成将直接揭示 噪声性耳蜗性突触变性和隐蔽听力的分子机制 损失。这些新的研究还将为针对噪声诱导的听力开辟一条新的治疗途径 丧失和耳蜗性突触。

SUMMARY The long-term goal of this project is to investigate mechanisms underlying noise-induced cochlear synaptopathy and hidden hearing loss. Noise is a common risk factor for hearing loss. Recent studies have demonstrated that even a single episode of noise overexposure induces transient hearing loss, i.e., temporal threshold shift (TTS), noise-exposed animals could have no hair cell loss but have extensive spiral ganglion neuron (SG) and synapse degeneration. In particular, low spontaneous rate (LSR) auditory nerves and their synaptic connections with inner hair cells are preferentially lost. The noise-exposed animals and humans demonstrate normal hearing threshold and sensitivity (i.e., hidden hearing loss) in the early stage but will eventually exhibit other hearing disorders and hearing loss. Currently, the underlying mechanism for such cochlear synaptopathy remains unclear. Noise stimulates hair cell and neuron over-activation and increases K+ efflux that leads to increasing extracellular K+ concentration. It is well-established that high extracellular K+ can induce toxicity leading to second cell death in the brain following injury and stroke. We hypothesize that high, excess extracellular K+ following noise exposure can also cause SG synapse and neuron degeneration in the cochlea. We previously found that ATP purinergic P2X receptors in the cochlea are required for sinking K+ to re-enter into cells. A recent study also demonstrated that P2X2 receptors are necessary for the development of TTS. In addition, we found that P2X2 mutation can increase susceptibility to noise and induce hearing loss. These studies indicate that P2X receptors may have a critical role in noise-induced cochlear synaptopathy and hidden hearing loss. In this project, we will first test whether high extracellular K+ can cause SG synapse and neuron degeneration (Specific Aim 1, SA1). Then, we will identify and characterize P2X receptor expression in SG neurons, including LSR and HSR (high spontaneous rate) fiber synaptic endings, and test whether P2X receptors can mediate K+-sinking in the SG neurons. In SA3, we will test whether deficiency of P2X receptors can induce and exacerbate cochlear synaptopathy and hearing loss following noise exposure and high-K+ challenge. Completion of these studies will directly reveal the molecular mechanism underlying noise-induced cochlear synaptic degeneration and hidden hearing loss. These novel studies will also open a new therapeutic avenue for targeting noise-induced hearing loss and cochlear synaptopathy.