Retrograde signaling and the modulation of short-term plasticity at an auditory synapse

项目摘要 听觉神经元的神经末梢负责突触的有效释放和再循环， 囊泡，使安全的化学传输，基础听觉。忠诚和 这些突触事件的调节在哺乳动物的上级橄榄复合体（SOC）中是重要的 脑干，其参与声源定位。Held神经终末的盏是一个完整的 这一传入投射途径的组成部分，从球状丛状细胞（GBC）的项目， 前腹侧耳蜗核（aVCN）和突触到内侧核的主细胞（PC） 梯形体（MNTB）。Held-MNTB突触的花萼特异性地参与 来自在每个耳蜗发起的声音提示的耳间强度差异。尽管众所周知 突触功效在急性时间尺度上响应于先前的活动而改变， 调节听觉脑干中突触强度的短期修饰需要进一步研究。 本文提出的工作旨在了解逆行信号如何调节突触前短期 可塑性（STP）在小鼠杯Held-MNTB突触。这种突触的一个特点是 在高频传输（即在体内频率≥ 800 Hz）期间的突触保真度， 传统的突触结不能可靠地激发。局部离子环境的纳米域调节是一种 公认的突触传递信号机制。由于高保真度的必要性， 在这个突触的功能输出中，听觉突触的细胞外突触K+积累可能更高 比传统的突触终扣在持续的尖峰活动。我们假设当地的微环境 在突触间隙的毫微微升体积中的K+有助于在突触间隙中STP的活性依赖性调节。 突触前神经末梢本项目的目的是1）确定细胞外的稳态调节 2）确定突触后去极化如何调节胞浆Ca 2+浓度 在成熟的突触前神经末梢; 3）确定逆行信号如何调节突触前STP。到 为了实现这些目标，结合小鼠遗传学、突触电生理学和Ca 2+成像方法， 将用于这项拨款提案的结果将提供对突触强度内在调制的见解 和可塑性在发展和成熟的听觉系统的突触。这将导致更好地理解 健康人的空间听觉和揭示治疗听力障碍的潜在突触机制。

Project Summary The nerve terminals of auditory neurons are responsible for the efficient release and recycling of synaptic vesicles that enable the secure chemical transmission that underlies auditory perception. The fidelity and modulation of these synaptic events is important in the superior olivary complex (SOC) of the mammalian brainstem, which is involved in sound source localization. The calyx of Held nerve terminal is an integral component of this afferent projection pathway, which projects from the globular bushy cells (GBCs) of the anteroventral cochlear nucleus (aVCN) and synapses onto the principal cells (PCs) of the medial nucleus of the trapezoid bodies (MNTB). The calyx of Held-MNTB synapse contributes specifically to the transduction of interaural intensity differences from sound cues initiated at each cochlea. Although it is well-established that synaptic efficacy changes at an acute timescale in response to previous activity, the underlying mechanisms regulating short-term modifications in synaptic strength in the auditory brainstem require further investigation. The work proposed here seeks to understand how retrograde signaling regulates presynaptic short-term plasticity (STP) at the mouse calyx of Held-MNTB synapse. A hallmark of this synapse is the ability to maintain synaptic fidelity during high frequency transmission (i.e. at frequencies ≥ 800 Hz in vivo), a range at which conventional synaptic boutons cannot reliably fire. The nano-domain regulation of local ionic environments is a well-accepted signaling mechanism of synaptic transmission. Because of the high-fidelity necessary for the functional output of this synapse, extracellular synaptic K+ accumulation is likely higher at auditory synapses than traditional synaptic boutons during persistent spiking activity. We hypothesize that local microenvironments of K+ in the femtoliter volume of the synaptic space contributes to the activity-dependent regulation of STP at the presynaptic nerve terminal. The aims of this project are to 1) determine the homeostatic regulation of extracellular K+ during synaptic activity; 2) determine how postsynaptic depolarization regulates cytosolic Ca2+ concentration in the mature presynaptic nerve terminal; 3) determine how retrograde signaling modulates presynaptic STP. To pursue these aims, a combination of mouse genetics, synaptic electrophysiology and Ca2+ imaging approaches will be used. The results of this grant proposal will provide insights on the intrinsic modulation of synaptic strength and plasticity at developing and mature synapses of the auditory system. This will lead to a better understanding of healthy human spatial hearing and reveal potential synaptic mechanisms for treating hearing disorders.