Synaptic specialization of auditory hair cells

听觉毛细胞的突触特化

• 批准号: 7600679
• 负责人: Anthony J Ricci
• 金额: $ 35.59万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-08 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600679
• 关键词: Action Potentials; Address; Amaze; Auditory; Auditory system; Cells; Data; Electrons; Ensure; Enzymes; Face; Fatigue; Fiber; Frequencies; Generations; Genetic Programming; Goals; Hair Cells; Image; Individual; Interruption; Intervention; Kinetics; Knowledge; Location; Measures; Modality; Modeling; Neuraxis; Neurons; Noise; Optics; Paired Comparison; Peripheral; Phase; Phosphorylation; Preventive Intervention; Process; Property; Regulation; Sensory; Site; Speed; Stimulus; Structure; Synapses; Synaptic Transmission; Techniques; Technology; Time; Variant; Vesicle; Work; computerized data processing; deafness; density; design; electrical property; hearing impairment; immunocytochemistry; new technology; novel; photolysis; postsynaptic; presynaptic; public health relevance; receptor; research study; response; spiral ganglion; synaptic function; tissue preparation; tool; trafficking; transmission process; two-photon; voltage

DESCRIPTION (provided by applicant): The peripheral auditory system communicates with the central nervous system through synapses between the sensory cells and the spiral ganglion neurons. This single synapse carries information regarding frequency, intensity and timing that is used by the CNS for to extract all information provided by the auditory modality. The synapse is specialized to operate across a broad frequency range, to respond to graded stimuli in a linear manner. The synapse maintains high rates of release and does not fatigue and is sensitive to receptor potentials often below 1 mV. The goal of this proposal is to delineate the mechanisms underlying these unusual synaptic properties. Both pre and postsynaptic mechanisms will be investigated. Specific Aim 1 addresses presynaptic issues and has three subaims; to identify the Ca2+ dependent components of vesicle release and trafficking, to determine the kinetics of release while identifying the rate limiting steps of trafficking and release, and to elucidate tonotopic differences in release properties, characterizing Ca2+ homeostatic mechanisms that regulate release and identifying phosphorylation dependent regulation of release and trafficking. Specific Aim 2 investigates postsynaptic processing with three goals; first to determine if there are tonotopic variations in afferent electrical properties that might serve to enhance frequency selectivity such as the kinetics and magnitude of voltage-dependent processes, second to characterize synaptic transmission at different locations to identify differences in receptor types and numbers and third to investigate mechanisms associated with multivesicular release. Structural, immunocytochemical, optical, electrophysiological and theoretical tools including several new technologies are included to better enable us to investigate these issues. Given that any deficits in synaptic transmission at the hair cell afferent fiber synapse results in auditory deficits, identifying novel mechanisms may provide unique avenues for intervention. PUBLIC HEALTH RELEVANCE All of the signal processing that happens at the auditory periphery is communicated to the central nervous system through the hair cell afferent fiber synapse. Any action that results in a loss of fidelity of this synapse leads to hearing loss and deafness. The requirements of this synapse are quite demanding and result in several unique specializations including: a graded and linear response to stimulus, an amazing lack of fatigue in the face of continual and often high release rates and postsynaptic firing rates, and the ability to phase-lock across several orders of magnitude of frequencies. Mechanisms underlying these specialized properties are unknown but should offer sites for intervention and prevention of noise induced and even ototoxic induced hearing loss. The primary goal of this work is to identify and characterize these mechanisms.

描述（由申请人提供）：外周听觉系统通过感觉细胞和螺旋神经节神经元之间的突触与中枢神经系统进行通信。这个单个突触携带有关频率、强度和时间的信息，中枢神经系统使用这些信息来提取听觉模态提供的所有信息。突触专门在较宽的频率范围内运行，以线性方式响应分级刺激。突触保持高释放率并且不会疲劳，并且对通常低于 1 mV 的受体电位敏感。该提案的目标是描述这些不寻常的突触特性背后的机制。突触前和突触后机制都将被研究。具体目标 1 解决突触前问题并具有三个子目标；确定囊泡释放和运输的 Ca2+ 依赖性成分，确定释放动力学，同时确定运输和释放的限速步骤，并阐明释放特性的音调差异，表征调节释放的 Ca2+ 稳态机制并确定磷酸化依赖性调节释放和贩运。具体目标 2 通过三个目标研究突触后处理；首先确定传入电特性是否存在音调变化，这些变化可能有助于增强频率选择性，例如电压依赖性过程的动力学和幅度，其次是表征不同位置的突触传递，以确定受体类型和数量的差异，第三是研究与多囊泡释放相关的机制。其中包括结构、免疫细胞化学、光学、电生理学和理论工具，包括几种新技术，以便我们更好地研究这些问题。鉴于毛细胞传入纤维突触的任何突触传递缺陷都会导致听觉缺陷，识别新机制可能会提供独特的干预途径。公共健康相关性 听觉周边发生的所有信号处理均通过毛细胞传入纤维突触传达至中枢神经系统。任何导致该突触失去保真度的行为都会导致听力损失和耳聋。这种突触的要求相当苛刻，并导致了几种独特的专业化，包括：对刺激的分级和线性响应，面对持续且经常高的释放速率和突触后放电速率时惊人地缺乏疲劳，以及阶段性的能力锁定几个数量级的频率。这些特殊特性的机制尚不清楚，但应该为干预和预防噪声引起的甚至耳毒性引起的听力损失提供场所。这项工作的主要目标是识别和表征这些机制。