Regulation of Synaptic Vesicle Dynamics in the Auditory System

 描述(申请人提供)：我们的长期目标是了解突触囊泡释放和恢复的机制，这些机制允许在不同的时间尺度上在广泛的动态范围内对声音进行准确编码。听觉脑干中Hold/MNTB突触的花冠是这一通路中的关键连接，因为它提供精确的时间并激活对关键双耳细胞群的持续抑制。它的巨大体积使其成为了解这些突触连接的机制和功能的实验切入点。花萼可以在高频率下由声音驱动，在不同的自发放电率的背景下工作，但必须相对不受声学噪声背景的影响。这是如何实现的？由于突触前具有有限的融合能力的突触小泡(SVS)，被称为易释放池(RRP)，RRP的释放和补充必须平衡才能维持传递。启动，即在活动区(AZ)产生具有融合能力的SVS，可响应动作电位(AP)释放，是调节RRP释放和补充以维持递质释放的关键调控途径。最终，调节启动的分子机制是支持声音编码的SVS有效释放和补充的基础。因此，我们的目标是确定分子机制，以确保释放能力强的SVS在广泛的AP放电频率范围内可用，以支持听觉加工的早期阶段。由于RRP的释放和补充是所有突触在不同时间尺度上编码信息所必需的，我们的数据将对理解突触通信如何导致神经网络中的信息传递具有广泛的相关性。

 DESCRIPTION (provided by applicant): Our long term goal is to understand the mechanisms of synaptic vesicle release and recovery that permit the accurate encoding of sound over wide dynamic ranges over varying times scales. The calyx of Held/MNTB synapse in the auditory brainstem is a key connection in this pathway since it provides precise timing and activates sustained inhibition to key binaural cell groups. Its large size has made it an experimentally accessible entry point into understanding the mechanisms and function of these synaptic connections. The calyx can be driven by sound at high rates, operates in the background of varying spontaneous firing rates, and yet must be relatively immune to acoustically noisy backgrounds. How is this achieved? Since the presynapse has a finite supply of fusion competent synaptic vesicles (SVs), termed the readily releasable pool (RRP), the release and replenishment of the RRP must be balanced to sustain transmission. Priming, the creation of fusion competent SVs at the active zone (AZ) that can be released in response to action potentials (APs), is a key regulatory pathway that regulates the RRP release and replenishment to sustain transmitter release. Ultimately, the molecular mechanisms that regulate priming underlie efficient release and replenishment of SVs underpins sound encoding. Therefore we aim to define the molecular mechanisms that ensure availability of release competent SVs throughout a wide range of AP firing rates to support the early stages of auditory processing. As release and replenishment of the RRP is necessary in all synapses to encode information over varying timescales, our data will have broad relevance to understanding how synaptic communication leads to information transfer in neural networks.