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.

摘要 间隙连接（GJ）介导的电突触是近年来发现的重要神经网络的基础 耳蜗背核的特性和解剖学证据表明，它们沿着 听觉通路然而，听觉电突触的性质仍然知之甚少。作为他们的 化学对应物，电突触是“可塑的”，也就是说，它们随着活动而改变它们的强度。变化 电突触的强度动态地重新配置各种神经结构中的神经元回路。 因此，电突触的存在和可塑性可以从根本上改变我们的认知方式。 了解听觉回路的组织，并最终了解听觉信息的处理。这 该提案旨在通过以下方式帮助我们理解听觉系统中的电传输 调查分子机制，造成塑料变化的GJ通信在混合，电气和 一种化学物质，将初级听觉传入耦合到鱼类的Mauthner（M-）细胞。我们在金鱼方面的工作 表明，在这些混合突触的电（和化学）传输经历活动依赖 增强作用因为这些动态特性后来被发现发生在哺乳动物的电突触上。 M细胞混合突触被认为是研究脊椎动物电传递可塑性的一个有价值的模型。 与化学突触相反，对神经元突触变化的分子机制知之甚少。 电突触的强度目前认为，GJ电导的塑性变化是由于直接 修改现有信道的属性。然而，我们的进展表明， GJ通道的插入和去除也可能有助于可塑性。我们建议调查 GJ通道的调节运输对电传输可塑性变化的贡献及其 分子基础为了直接检验这种可能性，我们将这些独特的混合突触模型 通过研究它们在斑马鱼幼体中的特性，将分析提高到一个新的水平。斑马鱼的顺从性 幼虫成像荧光标记的GJ通道在体内的运动应该允许监测活性 经历可塑性的突触。这一方法将为分析 电传输，详细的分子机制将通过结合体内 成像、电生理学和时间分辨超微结构分析以及强大的遗传操作。目的 1的目的是研究斑马鱼幼鱼电突触发生增强的条件。通过 结合电生理学和药理学与电和光遗传学刺激，这一目标将确定 幼虫混合突触经历电（和化学）增强的条件 传输目的2是测试是否需要插入和取出GJ通道以进行塑料变更。 这一目标将探讨电突触是复杂的突触结构的概念， 它们的正常功能和调节来自于多种蛋白质之间的相互作用。的 描述参与其调节的新分子机制将有助于更好地理解 与听觉功能障碍相关的电路的动力学和新的治疗方法的潜在识别 目标的