Plasticity of auditory electrical synapses

听觉电突触的可塑性

• 批准号: 9310995
• 负责人: Alberto E Pereda
• 金额: $ 60.3万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310995
• 关键词: Adult; Anatomy; Auditory; Auditory system; Behavior; Cells; Chemical Synapse; Chemicals; Chemosensitization; Communication; Complement; Complex; Connexins; DNA Sequence Alteration; Data; Dopamine; Electrical Synapse; Electron Microscopy; Electrophysiology (science); Excision; Fishes; Freezing; Functional disorder; Gap Junctions; Goldfish; Image; Larva; Life; M cell; Mediating; Methods; Microscopy; Modeling; Modification; Molecular; Monitor; Movement; Neuromodulator; Neurotransmitter Receptor; Optics; Pharmacology; Plasticizers; Property; Proteins; Protocols documentation; Regulation; Reporting; Research; Scaffolding Protein; Structure; Synapses; Synaptic Transmission; Testing; Time; Transgenic Organisms; Work; Zebrafish; auditory pathway; auditory processing; base; dorsal cochlear nucleus; electrical property; gap junction channel; genetic manipulation; genetic regulatory protein; in vivo; in vivo imaging; information processing; membrane flux; neural circuit; neuronal circuitry; new therapeutic target; novel; optogenetics; relating to nervous system; trafficking; transmission process

Abstract Gap junction (GJ)-mediated electrical synapses were recently reported to underlie important network properties in the dorsal cochlear nucleus and anatomical evidence suggests they are widespread along the auditory pathway. However, the properties of auditory electrical synapses remain poorly understood. As their chemical counterparts, electrical synapses are ‘plastic’, that is, they modify their strength with activity. Changes in the strength of electrical synapses dynamically reconfigure neuronal circuits in various neural structures. Thus, the presence and plastic properties of electrical synapses could fundamentally change the way we understand the organization of auditory circuits and, ultimately, the processing of auditory information. This proposal aims to contribute to our understanding of electrical transmission in the auditory system by investigating the molecular mechanisms causing plastic changes in GJ communication at mixed, electrical and chemical, contacts that couple primary auditory afferents to the Mauthner (M-) cells in fish. Our work in goldfish shows that electrical (and chemical) transmission at these mixed synapses undergo activity-dependent potentiation. Because these dynamic properties were later found to occur at mammalian electrical synapses. M-cell mixed synapses are considered a valuable model to study plasticity of vertebrate electrical transmission. In contrast to chemical synapses, little is known about the molecular mechanisms that underlie changes in the strength of electrical synapses. It is currently thought that plastic changes in GJ conductance are due to direct modification of the properties of already existing channels. However, our progress suggests that regulated insertion and removal of GJ channels may also contribute to plasticity. We propose to investigate the contribution of regulated trafficking of GJ channels to plastic changes of electrical transmission and its molecular underpinnings. To directly examine this possibility, we will take these unique model mixed synapses to a new level of analysis by investigating their properties in larval zebrafish. The amenability of zebrafish larvae to image the movement of fluorescently-tagged GJ channels in-vivo should allow monitoring of active synapses undergoing plasticity. This approach will provide an unprecedented window for the analysis of electrical transmission at which detailed molecular mechanisms will be investigated by combining in-vivo imaging, electrophysiology and time-resolved ultrastructural analysis with powerful genetic manipulations. Aim 1 is to investigate the conditions under which electrical synapses in larval zebrafish undergo potentiation. By combining electrophysiology and pharmacology with electrical and optogenetic stimulation, this aim will identify the conditions under which larval mixed synapses undergo potentiation of electrical (and chemical) transmission. Aim 2 is to test whether insertion and removal of GJ channels are required for plastic changes. This aim will explore the notion that electrical synapses are complex synaptic structures at which channels turnover and that their proper function and regulation results from interactions between multiple proteins. The description of novel molecular mechanisms involved in their regulation will contribute to a better understanding of the dynamics of circuits relevant to auditory dysfunction and the potential identification of novel therapeutic targets.

抽象的 GAP连接点（GJ）介导的电力突触最近据报道是重要的网络 背部耳蜗核和解剖学证据的特性表明它们沿着 听觉路径。但是，听觉电突触的特性仍然很少了解。作为他们 化学对应物，电突触是“塑料”，也就是说，它们通过活动来改变其强度。更改 电气突触的强度，在各种神经元结构中动态重新配置神经元回路。 这，电突触的存在和塑性特性可以从根本上改变我们的方式 了解听觉圈的组织，并最终了解听觉信息的处理。这 提案旨在通过通过 研究分子机制，导致混合，电气和 化学，接触了将原始听觉传入与鱼类中的Mauthner（M-）细胞的接触。我们在金鱼中的工作 表明这些混合突触处的电动（和化学）传播依赖于活动 增强。因为后来发现这些动态特性发生在哺乳动物的电突触处。 M细胞混合突触被认为是研究脊椎动物电气传播的可塑性的宝贵模型。 与化学突触相反，对基于变化的分子机制知之甚少 电突触的强度。目前认为GJ电导中的塑料变化是由于直接导致的 修改已经存在的渠道的属性。但是，我们的进步表明受监管 插入和去除GJ通道也可能有助于可塑性。我们建议调查 GJ通道受管贩运对电气传输的塑性变化及其的贡献 分子基础。为了直接检查这种可能性，我们将采用这些独特的模型混合突触 通过研究其在幼虫斑马鱼中的特性来进行新的分析水平。斑马鱼的合理性 幼虫，以形象荧光标记的GJ通道的运动，应允许监视活动 突触经历可塑性。这种方法将为分析的前所未有的窗口提供 电气传输将通过组合体内研究详细的分子机制 具有强大的遗传操作的成像，电生理学和时间分辨的超微结构分析。目的 1是为了研究幼虫斑马鱼中的电突触的条件。经过 将电生理学和药理学与电气和光遗传学刺激相结合，该目标将确定 幼虫混合突触经历电气（和化学）的增强条件 传播。 AIM 2是测试塑料变化是否需要插入和去除GJ通道。 这个目标将探讨电气突触是复杂的突触结构的观念 营业额和适当的功能和调节是由多种蛋白质之间的相互作用而产生的。这 对其调节所涉及的新分子机制的描述将有助于更好地理解 与听觉功能障碍有关的电路动力学和新型治疗的潜在识别 目标。