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射 声音刺激很长一段时间。这种高频射击接力 通过突触进行精确的计时，直到听觉脑干核的声音 信息处理。要完成此任务，突触必须维护 在整个火车上释放发射器。基础机制 重复刺激期间持续的发射器释放不好 在听觉突触上理解。我提出了一个新模型来说明持续的 在听觉突触中发射器释放。该模型由三个组成 假设。首先，重复刺激期间持续释放是由于 两者都可以快速补充可立即可用于的囊泡池 释放（可释放的池）和此池的分数（F）减少 每个冲动都发布。 F的减少可能使突触可以维持 发射机释放更长的时间，因为它减慢了耗竭的速率 重复刺激期间可释放的池。其次，f的减少 是由于释放机械对Ca2+的亲和力的降低而引起的 第三，补充是迅速的，但与刺激强度无关 CA2+我们将分别以三个目标测试这三个假设 大鼠梯形体的内侧核中的花萼型突触 听觉脑干。我们将监视神经终端处的膜电容， 这允许更直接地测量可释放的池尺寸和F。我们 将确定在 高频发射既取决于F的减少和快速补充 可释放的池（AIM 1）。我们将增加Ca2+浓度 笼中Ca2+化合物的光解并确定是否亲和力是 在重复刺激期间，释放机械到Ca2+会减少（AIM 2）。 最后，我们将确定补给率是否由 Ca2+缓冲液EGTA或通过刺激的频率和持续时间 通过光解的基底Ca2+浓度增加了笼子的光解 Ca2+化合物（AIM 3）。这些研究将提高我们对听力的理解 通过揭示持续发射器释放的机制来实现机制 Durng重复射击，这对于传达声音信息至关重要