Sustained transmitter release during repetitive firing

重复发射期间发射器持续释放

• 批准号: 6523626
• 负责人: LING-GANG WU
• 金额: $ 19.25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-24 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6523626
• 关键词: acoustic nerve; auditory nuclei; auditory pathways; brain electrical activity; calcium flux; cell population study; chelating agents; electrostimulus; hearing; laboratory rat; neural information processing; neurotransmitter metabolism; neurotransmitter transport; statistics /biometry; synapses; voltage /patch clamp

DESCRIPTION (provide by applicant) Auditory nerves may fire at high frequency for a long time upon sound stimulation. This high frequency firing is relayed with precise timing via synapses up to the auditory brainstem nuclei for sound information processing. To achieve this task, synapses must maintain transmitter release throughout the train of firing. The mechanism underlying sustained transmitter release during repetitive stimulation is not well understood at auditory synapses. I propose a new model to account for sustained transmitter release at auditory synapses. This model is composed of three hypotheses. First, sustained release during repetitive stimulation is due to both a rapid replenishment of a pool of vesicles immediately available for release (releasable pool) and a decrease in the fraction (F) of this pool being released by each impulse. The decrease in F may allow the synapse to sustain transmitter release for a longer time because it slows the rate of depletion of the releasable pool during repetitive stimulation. Secondly, the decrease in F is caused by a decrease in the affinity of the release machinery to Ca2+ Thirdly, replenishment is rapid, but independent of the stimulus intensity and Ca2+ We will test these three hypotheses with three aims, respectively, at a calyx-type synapse in the medial nucleus of the trapezoid body in the rat auditory brainstem. We will monitor membrane capacitance at the nerve terminal, which allows for more direct measurements of the releasable pool size and F. We will determine whether sustained release and relay of action potentials during high frequency firing rely on both a decrease in F and rapid replenishment of the releasable pool (Aim 1). We will increase the Ca2+ concentration by photolysis of the caged Ca2+ compound and determine whether the affinity of the release machinery to Ca2+ is decreased during repetitive stimulation (Aim 2). Finally, we will determine whether the rate of replenishment is regulated by the frequency and duration of stimulation, by the Ca2+ buffer EGTA, or by an increase in the basal Ca2+ concentration induced by photolysis of the caged Ca2+ compound (Aim 3). These studies will improve our understanding of hearing mechanisms by revealing mechanisms underlying sustained transmitter release durng repetitive firing, which is critical for conveying sound information

描述(由申请人提供)听觉神经可能以高频发出 在很长一段时间内对声音进行刺激。这种高频发射是转播的 通过突触到达听觉脑干核团进行精确的声音计时 信息处理。为了完成这项任务，突触必须保持 发射器在整个发射过程中释放。其背后的机制 重复刺激期间持续的递质释放不好 在听觉突触上被理解。我提出了一个新的模型来解释持续 在听觉突触释放递质。该模型由三个部分组成 假设。首先，重复刺激期间的持续释放是由于 既可以快速补充囊泡池，又可以立即用于 释放(可释放池)和该池的分数(F)的减少 每一次冲动都会释放。F的减少可能使突触得以维持 发射器释放时间更长，因为它减缓了 重复刺激时的可释放池。其次，F的减少 是由于释放机制对钙离子的亲和力降低所致 第三，补给是快速的，但与刺激强度和 CA2+我们将分别以三个目标检验这三个假说： 大鼠斜方体内侧核的帽状突触 听觉脑干。我们将监测神经末梢的膜电容， 这允许更直接地测量可释放池的大小和F。 将决定动作电位的持续释放和传递在 高频激发既依赖于F的减少，也依赖于对 可释放池(目标1)。我们将通过以下方式提高钙离子浓度 笼状Ca~(2+)化合物的光解并确定其亲和力是否 重复刺激时，钙释放机制减少(目标2)。 最后，我们将确定补给率是否受到以下因素的监管 刺激的频率和持续时间，由钙离子缓冲剂EGTA或由一个 笼养动物光解引起的基础钙离子浓度升高 钙离子化合物(目标3)。这些研究将提高我们对听力的理解 通过揭示递质持续释放的机制来实现 在重复发射过程中，这对于传递声音信息至关重要