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对于 听证会在最初的几个听觉处理站中编码这些信息需要 可靠和精确的突触传递，以响应向上的快速和大的波动。 到千赫兹范围的动作电位（AP）放电率。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 必须维持快速和重复的SV释放以编码声音信息。因此，声音 编码对SV释放和补充的时间动力学提出了很高的要求。一 调节AP诱发SV释放的关键步骤是启动，这是产生融合能力的过程 SV非常接近电压门控CaV 2通道（CaV）。启动率和SV 补充高度依赖于突触前Ca 2+通过CaV 2通道的大小。 调节引发的分子中的人类突变导致SV释放的失调， 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）是编码声音定位和时间的关键 音乐中的声音特征和动物发声到人类语言中的交流。 GBC轴突形成Held的花萼，Held是一个突触前神经末梢，是唯一的输入 在MNTB中驱动AP尖峰。花萼利用快速SV释放动力学来传递模式 耳蜗核传入AP峰电位到MNTB。这反过来又会导致快速和 精确抑制关键的单声道和双耳细胞群。正在出现的是，异常的MNTB 信号是老龄化人群中声音定位和言语感知缺陷的基础， 可能导致神经系统疾病中的中枢听觉缺陷。因此，我们的目标是 阐明调节SV释放时间动态的分子机制， 补充所需的适当的听觉信息处理。鉴于必须 引发突触传递，以及异常SV的病理后果 我们的研究结果将提供关于信息是如何被编码的基本见解。 神经系统，并预计将促进治疗的发展，为广泛的 神经和神经精神障碍。

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.