Regulation of Synaptic Vesicle Dynamics in the Auditory System

听觉系统突触小泡动力学的调节

• 批准号: 10194445
• 负责人: Samuel Matthew Young
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10194445
• 关键词: Actins; Action Potentials; Animal Vocalization; Auditory; Auditory Perceptual Disorders; Auditory system; Automobile Driving; Axon; Behavioral; Binaural; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Central Auditory Processing Disorder; Cochlear nucleus; Communication; Cytoskeleton; Data; Defect; Electron Microscopy; Evoked Potentials; Frequencies; Glutamates; Goals; Hearing; Hearing problem; Human; Intellectual functioning disability; Kinetics; Knock-out; Knockout Mice; Link; Location; Mammals; Medial; Molecular; Mus; Music; Mutation; Nervous system structure; Neurons; P-Q type voltage-dependent calcium channel; Pathologic; Pathway interactions; Pattern; Physiological; Presynaptic Terminals; Probability; Process; Publishing; Regulation; Research; Role; Signal Transduction; Slice; Sound Localization; Source; Speech; Speech Perception; Speech Sound; Spike Potential; Stimulus; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Techniques; Testing; Viral Vector; Whole-Cell Recordings; aging population; auditory processing; autism spectrum disorder; base; conditional knockout; gutless adenoviral vector; in vivo; information processing; insight; mouse model; mutant; negative affect; nervous system disorder; neuropsychiatric disorder; novel; operation; presynaptic; response; sound; synaptic depression; therapy development; trapezoid body; vesicular release; voltage

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.

项目摘要/摘要 定位声源和检测声音的时间特征的能力至关重要 听力。在前几个听觉处理站中编码此信息需要 可靠，精确的突触传播，以响应于快速和大波动的响应 到Kilohertz的动作电势（AP）射击率。但是，突触的数量 可用于AP诱发的释放的囊泡（SVS）受到限制。许多听觉的脑干突触 必须维持快速和重复的SV版本以编码声音信息。因此，声音 编码对SV发布和补货的时间动态的巨大要求。一个 调节AP引起的SV版本的关键步骤是启动的，该过程创建了融合能力 靠近电压门控CAV2通道（CAV）的SVS。启动和SV的速率 补充高度取决于通过CAV2通道突触前Ca2+的大小。 调节启动的分子中的人类突变导致SV释放失调，这 是许多听觉和神经系统疾病的原因。 在哺乳动物中，球状灌木细胞（GBC）与内侧核之间的途径 梯形身体神经元（MNTB）对于编码声音定位和时间至关重要 在动物发声中发现的音乐和传播中的声音特征。 GBC轴突形成固定的花萼，一种谷氨酸能突触前末端，即唯一输入 这使MNTB中的AP尖峰驱动。 Calyx使用快速的SV释放动力学来中继模式 MNTB的人工耳蜗核中的传入AP峰值。反过来，这导致了迅速的 精确抑制关键的单膜细胞组。正如异常的mntb正在出现的 信号传导是衰老人口的声音定位和语音感知缺陷的基础 可以促进神经系统疾病中的中央听觉缺陷。因此，我们的目标是 描述调节SV释放时间动力学的分子机制和 适当的听觉信息处理所需的补充。考虑到重要性 突触传播中的启动以及异常SV的病理后果 发布，我们的发现将提供有关信息如何编码的基本见解 神经系统，有望促进开发广泛的治疗方法 神经和神经精神疾病。