Regulation of Synaptic Vesicle Dynamics in the Auditory System

项目摘要/摘要 定位声源和检测声音的时间特征的能力是 听证。在最初的几个听觉处理站内对这些信息进行编码需要 可靠而准确的突触传递，以应对向上快速而大幅的波动 至动作电位(AP)放电频率的千赫兹范围。然而，突触的数量 可用于AP诱发释放的囊泡(SVS)是有限的。许多听性脑膜突触 必须保持快速和重复的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。一个 调节AP诱发SV释放的关键步骤是启动，创造融合能力的过程 靠近电压门控CaV2通道(Cav)的SVS。引发率和SV 补给高度依赖于通过CaV2通道的突触前钙离子的大小。 调节启动的分子中的人类突变导致SV释放的失调 是许多听觉和神经疾病的原因。 在哺乳动物中，球状丛状细胞(GBCS)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 从动物发声到人类语言的音乐和交流中的声音特征。 GBC轴突形成Hold的花环，这是一个谷氨酸能突触前终末，是唯一的输入 这推动了AP在MNTB中的激增。花萼使用快速的SV释放动力学来传递图案 位于MNTB的耳蜗核的传入AP棘波。这反过来又导致了快速和 精确抑制关键的单耳和双耳细胞组。出现了异常的MNTB 信号是老龄化人口中声音定位和言语感知缺陷的基础 会导致神经系统疾病中的中枢性听觉缺陷。因此，我们的目标是 为了阐明调控SV释放和释放时间动力学的分子机制 适当的听觉信息处理所需的补充。鉴于……的重要性 突触传递中的启动以及异常SV的病理后果 发布后，我们的发现将提供有关信息如何由 并有望促进治疗多种疾病的治疗方法的开发 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.