Synaptic mechanisms of auditory information processing

听觉信息处理的突触机制

• 批准号: 10132290
• 负责人: Hai Huang
• 金额: $ 32.3万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132290
• 关键词: Action Potentials; Affect; Attention; Auditory; Auditory system; Brain Stem; Cell membrane; Complex; Cytosol; Data; Dialysis procedure; Dyes; Electric Capacitance; Endocytosis; Environment; Exocytosis; Frequencies; Future; Glutamates; Goals; Hearing problem; Image; Injury; Link; Maps; Measurement; Membrane; Methods; Modeling; Neurons; Neurotransmitters; Noise; Pathologic; Pharmacology; Phase; Physiological; Probability; Process; Property; Recycling; Regulation; Research; Role; Signal Transduction; Site; Synapses; Synaptic Transmission; Synaptic Vesicles; Vesicle; Work; falls; hearing impairment; information processing; insight; neurotransmitter release; neurotransmitter transport; normal hearing; postsynaptic; presynaptic; quantum; sound frequency; synaptic function; transmission process; treatment strategy; uptake; vesicular release

PROJECT SUMMARY The reliability and precision of synaptic transmission are required in circuits of the auditory brainstem in order to encode timing with submillisecond accuracy. Auditory information is encoded by action potentials phase-locked to sound frequency at high rates. Accordingly, synaptic vesicles need to be recycled and refilled rapidly. Accumulating studies have uncovered the processes of vesicle fusion and recycling; however, the control of the contents of synaptic vesicles has received considerably less attention. Reasons for this gap in our understanding include the small size of synaptic vesicles and of conventional synapses, the complex ionic basis for loading of neurotransmitter into vesicles, and the difficulty in manipulating and assessing vesicle loading in physiological conditions. We have recently found that a Na+/H+ exchanger expressed on synaptic vesicles promotes vesicle filling with glutamate. Using the calyx of Held, a giant glutamatergic synapse in the auditory brainstem that permits direct pre- and postsynaptic recordings and manipulation of the presynaptic cytosol, we showed that glutamate loading is facilitated by intracellular Na+ over the physiological concentration range. Na+ influx through presynaptic plasma membrane HCN channels affects presynaptic Na+ concentration, regulates glutamate uptake, and thus controls miniature excitatory postsynaptic currents. Here we propose that during high-frequency signaling, when large amounts of glutamate are released, Na+ accumulates in terminals and facilitates glutamate uptake into synaptic vesicle, accelerating vesicle replenishment and sustaining reliable synaptic transmission. We further hypothesize that the control of vesicle loading, release and recycling can be affected by hearing loss. This work will establish a new fundamental role of Na+ to link activity and synaptic function under physiological and pathological conditions.

项目总结 在听觉脑干的回路中，突触传递的可靠性和精确度是必需的，以便 以亚毫秒级精度编码计时。听觉信息由动作电位锁相编码 到高频率的声音频率。因此，突触小泡需要迅速回收和补充。 越来越多的研究揭示了囊泡融合和回收的过程；然而，对 突触小泡的内容受到相当少的关注。造成我们理解上的这种差距的原因 包括小尺寸的突触小泡和常规突触，加载 神经递质进入囊泡，以及在生理学中操纵和评估囊泡负荷的难度 条件。我们最近发现，表达在突触小泡上的一种Na+/H+交换器促进小泡 充满了谷氨酸。利用Hold的花冠，听觉脑干中的一个巨大的谷氨酸能突触 允许直接在突触前和突触后记录和操纵突触前胞浆，我们证明了 在生理浓度范围内，细胞内的Na+可以促进谷氨酸的负荷。Na+流经 突触前质膜HCN通道影响突触前Na+浓度，调节谷氨酸摄取， 从而控制微小的兴奋性突触后电流。在这里，我们建议在高频期间 信号，当大量谷氨酸释放时，Na+在终端积累并促进谷氨酸 摄取到突触小泡，加速小泡的补充，维持可靠的突触传递。 我们进一步假设，听力损失可能会影响囊泡装载、释放和回收的控制。 这项工作将建立一个新的基础作用，Na+联系活动和突触功能在生理 以及病态的情况。