Regulation of Synaptic Vesicle Dynamics in the Auditory System

项目概要/摘要 定位声源和检测声音的时间特征的能力是 听力。在最初的几个听觉处理站内编码此信息需要 可靠和精确的突触传递，以响应快速和大的向上波动 动作电位 (AP) 放电率达到千赫兹范围。然而，突触的数量 可用于 AP 诱发释放的囊泡 (SV) 是有限的。许多听觉脑干突触 必须维持快速且重复的 SV 释放来编码声音信息。因此，声音 编码对 SV 释放和补充的时间动态提出了很高的要求。一个 调节 AP 诱发的 SV 释放的关键步骤是启动，即产生融合能力的过程 SV 靠近电压门控 CaV2 通道 (CaV)。启动率和 SV 补充高度依赖于通过 CaV2 通道的突触前 Ca2 的大小。 人类调节启动的分子突变导致 SV 释放失调 是许多听觉和神经系统疾病的原因。 在哺乳动物中，球状丛状细胞 (GBC) 和内侧核之间的通路 梯形体神经元 (MNTB) 对于声音定位和时间编码至关重要 音乐中的声音特征以及动物发声与人类言语之间的交流。 GBC 轴突形成 Held 的花萼，Held 是一种谷氨酸能突触前末端，是唯一的输入 导致 MNTB 中的 AP 尖峰。花萼利用快速 SV 释放动力学来传递模式 耳蜗核中的传入 AP 尖峰到 MNTB。这反过来又导致快速且 精确抑制关键的单耳和双耳细胞群。异常的 MNTB 正在出现 信号传导是人口老龄化中声音定位和语音感知缺陷的基础 可能导致神经系统疾病中发现的中枢听觉缺陷。因此，我们的目标是 描述调节 SV 释放时间动态的分子机制 适当的听觉信息处理所需的补充。鉴于重要性 突触传递的启动，以及异常 SV 的病理后果 发布后，我们的研究结果将为信息如何被编码提供基本见解 神经系统，预计将促进多种治疗方法的开发 神经系统和神经精神疾病。

Project Summary/Abstract The ability to localize sound sources and detect temporal features of sound is fundamental to hearing. Encoding this information within the first few auditory processing stations requires reliable and precise synaptic transmission in response to rapid and large fluctuations of upwards to the kilohertz range in action potential (AP) firing rates. However, the number of synaptic vesicles (SVs) available for AP-evoked release is limited. Many auditory brainstems synapses must sustain fast and repetitive SV release to encode sound information. Therefore, sound encoding places great demands on the temporal dynamics of SV release and replenishment. A key step regulating AP evoked SV release is priming, the process that creates fusion competent SVs in close proximity to voltage-gated CaV2 channels (CaV). The rate of priming and SV replenishment is highly dependent on the magnitude of presynaptic Ca2+ through CaV2 channels. Human mutations in the molecules regulating priming result in dysregulation of SV release which is the cause of many auditory and neurological disorders. In mammals, the pathway between the globular bushy cells (GBCs) and the medial nucleus of the trapezoid body neurons (MNTB) is critical for encoding sound localization and temporal features of sound in music and communication found in animal vocalizations to human speech. The GBC axon forms the calyx of Held, a glutamatergic presynaptic terminal, that is the sole input that drives AP spiking in the MNTB. The calyx uses fast SV release kinetics to relay the patterns of afferent AP spikes in the cochlear nucleus to the MNTB. This, in turn, results in rapid and precise inhibition of key mono- and binaural cell groups. It is emerging that aberrant MNTB signaling underlies sound localization and speech perception defects in the aging population and can contribute to central auditory defects found in neurological disorders. Therefore, our goal is to delineate the molecular mechanisms regulating the temporal dynamics of SV release and replenishment required for proper auditory information processing. Given the importance of priming in synaptic transmission, as well as the pathological consequences of aberrant SV release, our findings will provide fundamental insights into how information is encoded by the nervous system and are expected to facilitate the development of treatments for a wide range of neurological and neuropsychiatric disorders.