Regulation of exo- and endocytosis at ribbon synapses of auditory hair cells

听觉毛细胞带状突触的外吞和内吞作用的调节

• 批准号: 8834855
• 负责人: Owen P Gross
• 金额: $ 5.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-10 至 2016-01-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834855
• 关键词: ATP phosphohydrolase; Acoustics; Address; Affect; Afferent Neurons; Agonist; Amphibia; Area; Auditory; Auditory Perception; Biochemical; Biological Assay; Brain; Buffers; Cell surface; Cells; Code; Complex; Cytoplasm; Data; Dependence; Docking; Ear; Electric Capacitance; Endocytosis; Ensure; Environment; Equilibrium; Event; Exhibits; Exocytosis; Fiber; Frequencies; Goals; Hair Cells; Hearing; Individual; Investigation; Isradipine; Lead; Life; Measurement; Measures; Membrane; Membrane Potentials; Methods; Modeling; Molecular; Nervous system structure; Neurons; Neurotransmitters; Output; Pathway interactions; Perception; Phase; Physiological; Play; Preparation; Process; Property; Protocols documentation; Protons; Pump; Rana catesbeiana; Receptor Signaling; Recycling; Regulation of Exocytosis; Research; Rest; Role; Series; Signal Transduction; Solutions; Stimulus; Structure; Synapses; Synaptic Vesicles; System; Testing; Time; Vertebrates; Vesicle; Visual; auditory discrimination; base; channel blockers; computerized tools; deafness; design; improved; mathematical model; neurotransmitter release; operation; patch clamp; postsynaptic; presynaptic; programs; protein complex; public health relevance; receptor; relating to nervous system; research study; response; ribbon synapse; sensory system; sound; synaptic function; tongue papilla; transmission process; vibration; visual information; voltage

DESCRIPTION (provided by applicant): Perception of the external world begins with transduction of physical stimuli into biochemical signals by receptor neurons. To propagate these signals throughout the nervous system, receptor neurons in both the auditory and visual information pathways of vertebrates employ specialized synapses characterized by a dense presynaptic structure known as a ribbon. Synaptic ribbons possess unique features thought to facilitate sustained, low-latency exocytosis of neurotransmitter in response to activation of the presynaptic transduction cascade. Disruption of ribbon synapse function in auditory hair cells, which detect acoustic vibrations, can cause deafness, demonstrating the central role of ribbons in auditory perception. More subtle observations of auditory ribbon synapses have revealed several puzzling properties that could influence functional encoding of auditory information. Specifically, measurements of neurotransmitter release from hair cells show simultaneous exocytosis of multiple vesicles, a phenomenon known as multivesicular release that represents a potential coding strategy for amplifying weak signals or for ensuring temporal precision of encoded auditory information. Additionally, in order to maintain a high rate of neurotransmitter release during sustained stimulation, the neurotransmitter vesicle pool must be continuously recycled, a process that involves endocytosis of previously fused vesicles. The mechanisms that regulate replenishment of the vesicle pool are poorly understood in hair cells, although observations from other neural systems provide clues about which intracellular signals might play regulatory roles in this process. Even less is known about the mechanisms that facilitate multivesicular release. These phenomena will be investigated using paired electrophysiological recordings from auditory hair cells and postsynaptic afferent fibers in the bullfrog (Rana catesbeiana) amphibian papilla. Experiments will be conducted using stimulation protocols and recording solutions specially designed to test the requirements for multivesicular release and the role of pH in controlling the rate of vesicle recycling. Computational tools will be developed for analyzing the instantaneous rate of exocytosis during complex evoked release events and for modeling presynaptic pH dynamics immediately following exocytosis. Results from these experiments have the potential to reveal molecular mechanisms and signaling strategies important not only to the process of auditory perception, but also to the general understanding of how sensory neurons encode and sustain information-rich signals describing a broad array of stimulus features.

描述（由申请人提供）：对外部世界的感知始于通过受体神经元将物理刺激转导向生化信号。为了在整个神经系统中传播这些信号，脊椎动物的听觉和视觉信息途径中的受体神经元采用特征在于致密的突触前结构的专门突触，称为色带。突触丝带具有独特的特征，以促进神经递质的持续持续，低延迟的胞吐作用，以响应于突触前转导级联反应。检测声振动的听觉毛细胞中色带突触功能的破坏会引起耳聋，这表明了丝带在听觉感知中的核心作用。对听觉功能区突触的更微妙的观察结果揭示了几种令人困惑的属性，这些特性可能影响听觉信息的功能编码。具体而言，从毛细胞中对神经递质释放的测量结果显示出多种囊泡的同时胞吐作用，这是一种称为多膜释放的现象，代表了扩增弱信号或确保编码听觉信息的时间精度的潜在编码策略。此外，为了在持续刺激期间保持高递质的神经递质释放速率，必须连续回收神经递质囊泡池，这一过程涉及先前融合的囊泡的内吞作用。尽管来自其他神经系统的观察结果提供了有关哪些细胞内信号可能在此过程中起调节作用的线索，但在毛细胞中尚不清楚调节囊泡池补充的机制。关于促进多弹性释放的机制的知之甚少。这些现象将使用来自听觉毛细胞和牛蛙（Rana Catesbeiana）两栖动物乳头上的听觉毛细胞和突触后传入纤维的配对电生理记录进行研究。实验将使用刺激方案和记录解决方案进行，专门设计用于测试多源释放的要求以及pH在控制囊泡回收速率中的作用。将开发计算工具，以分析复杂诱发的释放事件期间的胞外增生速率，并在胞吐作用后立即建模突触前pH动力学。这些实验的结果有可能揭示分子机制和信号传导策略，不仅对听觉感知过程很重要，而且还可以对感觉神经元如何编码和维持信息丰富的信息信号的一般理解，描述了广泛的刺激特征。