Synaptic specialization of auditory hair cells

听觉毛细胞的突触特化

• 批准号: 7992365
• 负责人: Anthony J Ricci
• 金额: $ 32.89万
• 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/7992365
• 关键词: Action Potentials; Address; Amaze; Auditory; Auditory system; Cells; Data; Electrons; Ensure; Enzymes; Fatigue; Fiber; Frequencies; Generations; Genetic Programming; Goals; Hair Cells; Health; 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; 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）：外围听觉系统通过感觉细胞和螺旋神经神经元之间的突触与中枢神经系统通信。该单个突触传递有关CNS用于提取听觉方式提供的所有信息的频率，强度和时机的信息。突触专门用于在较大的频率范围内运行，以线性方式响应分级刺激。突触保持较高的释放速度，不疲劳，并且对受体电位通常敏感，通常低于1 mV。该提案的目的是描述这些异常突触特性的基础机制。将研究前后突触后机制。特定的目标1解决了突触前问题，并有三个subiaim；为了确定囊泡释放和运输的Ca2+依赖性组成部分，以确定释放动力学的同时确定运输和释放的速率限制步骤，并阐明释放性能的体点差异，表征CA2+稳态机制，以调节释放和识别释放和释放和运输的磷酸化调节。特定目标2调查了三个目标的突触后处理；首先要确定传入的电性能是否存在调整，可能会提高频率选择性，例如电压依赖性过程的动力学和大小，其次是在不同位置表征突触传播以识别受体类型和数量的突触传播，而在研究机构中的第三种差异。包括结构，免疫细胞化学，光学，电生理和理论工具，包括几种新技术，以更好地使我们能够研究这些问题。鉴于在毛细胞传入纤维突触中突触传播的任何缺陷都会导致听觉缺陷，因此识别新型机制可能会为干预提供独特的途径。公共卫生相关性通过毛细胞传入纤维突触将听觉外围的所有信号处理传达给中枢神经系统。任何导致这种突触失去忠诚度的动作都会导致听力丧失和耳聋。该突触的要求非常苛刻，并导致了几种独特的特殊性，包括：面对持续且通常很高的释放速度和突触后射击率的刺激的分级和线性响应，以及在几个频率范围内相锁的能力。这些专业特性的基础机制尚不清楚，但应提供干预和预防噪声甚至耳毒引起的听力损失的地点。这项工作的主要目标是识别和表征这些机制。