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

听觉突触的逆行信号传导和短期可塑性的调节

• 批准号: 9982312
• 负责人: Brendan Lujan
• 金额: $ 1.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982312
• 关键词: Acute; Adolescent; Applications Grants; Astrocytes; Auditory; Auditory Perception; Auditory system; Biological Assay; Biological Models; Biophysics; Brain Stem; Brain region; Buffers; Cell Nucleus; Cells; Chemical Synapse; Chemicals; Cochlea; Cochlear nucleus; Complex; Cues; Data; Dependence; Development; Electrophysiology (science); Environment; Event; Extracellular Space; Fiber; Fire - disasters; Frequencies; Goals; Hearing; Hearing problem; Hippocampus (Brain); Hour; Human; Image; Investigation; Medial; Modeling; Modification; Mus; Nature; Nerve; Neuraxis; Neurons; Output; Pathway interactions; Pharmacology; Play; Preparation; Presynaptic Terminals; Probability; Recycling; Regulation; Role; Secure; Signal Pathway; Signal Transduction; Slice; Source; Synapses; Synaptic Cleft; Synaptic Potentials; Synaptic Transmission; Synaptic Vesicles; Techniques; Tissues; Work; conditional knockout; endocannabinoid signaling; experimental study; extracellular; imaging approach; in vivo; insight; millisecond; mouse genetics; nano; novel; patch clamp; postsynaptic; presynaptic; presynaptic neurons; response; sound; source localization; transmission process; trapezoid body; uptake

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.

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 小泡，使作为听觉基础的安全化学传输成为可能。保真度和 这些突触事件的调节在哺乳动物的上橄榄复合体(SOC)中很重要 脑干，参与声源定位。夹持的神经末梢的花环是一个整体 这一传入投射通路的组成部分，从丘脑的球状丛状细胞(GBCs)投射。 耳蜗前腹核(AVCN)和与内侧核主细胞(PC)的突触 梯形小体(MNTB)Hold-MNTB突触的信号转导具有特异性。 在每个耳蜗处启动的声音提示的耳间强度差异。尽管众所周知， 突触效率在急性时间尺度上的变化响应于先前的活动，潜在的机制 调节听觉脑干突触强度的短期变化需要进一步的研究。 这里提出的工作试图理解逆行信号如何调节突触前短期 Hold-MNTB突触的可塑性(STP)。这种突触的一个特点是能够维持 高频传输期间的突触保真度(即在活体内800赫兹的频率下)，在此范围内 传统的突触环不能可靠地发射。局部离子环境的纳域调节是一种 公认的突触传递信号机制。因为需要高保真度的图像 这种突触的功能输出，细胞外突触的K+积累在听觉突触可能更高 而不是在持续尖峰活动期间的传统突触活动。我们假设当地的微环境 在突触间隙的飞升体积中的K+参与了STP在 突触前神经末梢。这个项目的目的是：1)确定细胞外的动态平衡调节 突触活动期间的K+；2)确定突触后去极化如何调节胞浆内钙离子浓度 3)确定逆行信号如何调节突触前STP。至 追求这些目标，结合小鼠遗传学、突触电生理学和钙离子成像方法 将会被使用。这项拨款计划的结果将为突触强度的内在调节提供见解 以及听觉系统发育和成熟突触的可塑性。这将使我们更好地理解 并揭示了治疗听力障碍的潜在突触机制。