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.

项目概要 听觉脑干回路需要突触传递的可靠性和精确性，以便 以亚毫秒精度对时序进行编码。听觉信息由锁相动作电位编码 到高速率的声音频率。因此，突触小泡需要快速回收和重新填充。 不断积累的研究揭示了囊泡融合和回收的过程；然而，控制 突触小泡的内容物受到的关注要少得多。我们理解上存在这种差距的原因 包括突触小泡和常规突触的小尺寸，负载的复杂离子基础 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困难 状况。我们最近发现突触小泡上表达的 Na+/H+ 交换剂可促进囊泡 填充谷氨酸。利用 Held 的花萼，听觉脑干中的一个巨大的谷氨酸能突触， 允许直接突触前和突触后记录以及突触前细胞质的操作，我们证明 细胞内 Na+ 在生理浓度范围内促进谷氨酸负载。 Na+流入 突触前质膜 HCN 通道影响突触前 Na+ 浓度，调节谷氨酸摄取， 从而控制微型兴奋性突触后电流。这里我们建议在高频时 信号传导，当大量谷氨酸被释放时，Na+在末端积聚并促进谷氨酸 摄取到突触小泡中，加速小泡的补充并维持可靠的突触传递。 我们进一步假设，囊泡装载、释放和回收的控制可能会受到听力损失的影响。 这项工作将确立 Na+ 在生理条件下连接活动和突触功能的新基本作用 和病理状况。