Functional roles of electrical synapses formed by neuronal gap junctions

神经元间隙连接形成的电突触的功能作用

• 批准号: RGPIN-2015-03861
• 负责人: Nagy, James
• 金额: $ 2.4万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684730
• 关键词: Functional; roles; electrical; synapses; formed

Gap junctions are aggregates of intercellular communication channels formed by connexin proteins that have essential roles in cells throughout the body. When gap junctions occur between neurons, they create electrical synapses that mediate direct electrical communication between neurons. Nagy's group and others have revealed both the prevalence and importance of electrical synapses in many regions of mammalian brain and spinal cord. His research program is centered on two long-term objectives: i) deciphering the structural and regulatory protein components of electrical synapses; and ii) gaining knowledge of the functional roles of these synapses in neuronal circuitry. Proposed work on the latter objective aims to provide basic understanding of the occurrence and requirements for electrical synapses in three different neuronal systems each of which govern fundamentally important physiological processes. They hypothesize that electrical synapses confer novel functional properties and contribute essential synchronizing mechanisms that are key to neuronal activity in each of these systems and the functions these systems subserve.***The three systems to be examined include: i) Primary afferent unmyelinated sensory C-fibers that have many important functions, including mediation of the physiologically critical peripheral axon reflex. These fibers were reported to be electrically coupled decades ago, but the basis for this coupling remains unknown. Nagy recently found evidence for the presence of the gap junction forming protein connexin36 in sensory neurons, and aims to establish that Cx36 mediates electrical coupling between sensory fibers, which would fundamentally shift understanding of the mechanistic basis of the axon reflex; ii) Sexually dimorphic motoneurons in spinal cord, which control bladder emptying and sexual activity and where Nagy's group recently found an abundance of electrical synapses formed by connexin36; and iii) Preganglionic sympathetic neurons in the spinal cord, where electrical synapses are known to occur, but nothing is known about the organization of these synapses or of their functional role, knowledge of which is required for a more complete understanding of how sympathetic neurons control a host of autonomic functions.***Nagy will use biochemical, anatomical and ultrastructural approaches in normal mice to identify sites where electrical synapses occur and physiological strategies in transgenic mice to establish how these synapses contribute to the operation of the systems to be examined. Results will add to emerging knowledge of the novel, intricate and critical roles these synapses play in neuronal circuitry, and will serve as translation of key mechanistic concepts surrounding electrical synapses to their importance in maintaining operations of whole organ physiology. **

缝隙连接是由连接蛋白形成的细胞间通讯通道的聚集体，在整个身体的细胞中具有重要的作用。当神经元之间发生缝隙连接时，它们会产生电突触，介导神经元之间的直接电通信。Nagy的团队和其他人揭示了电突触在哺乳动物大脑和脊髓的许多区域的普遍存在和重要性。他的研究计划集中在两个长期目标上：i)破译电子突触的结构和调节蛋白成分；ii)了解这些突触在神经回路中的功能作用。关于后一个目标的拟议工作旨在提供对三个不同神经系统中电突触的发生和要求的基本了解，每个神经系统都控制着根本上重要的生理过程。他们假设，电突触赋予了新的功能特性，并贡献了基本的同步机制，这些机制对这些系统中的神经元活动和这些系统所辅助的功能是关键的。*将被检查的三个系统包括：i)具有许多重要功能的初级传入无髓感觉C纤维，包括调节生理上关键的外周轴突反射。据报道，几十年前，这些纤维是电耦合的，但这种耦合的基础仍然不清楚。Nagy最近发现了在感觉神经元中存在缝隙连接形成蛋白Connecexin36的证据，并旨在建立Cx36介导感觉纤维之间的电耦合，这将从根本上改变对轴突反射机制基础的理解：ii)脊髓中的性别二态运动神经元，它控制着膀胱的排空和性活动，Nagy的团队最近发现了大量由Connecexin36形成的电突触；和iii)脊髓中的节前交感神经元，已知在那里发生电子突触，但对这些突触的组织或它们的功能作用尚不清楚，这些知识是更全面地了解交感神经元如何控制一系列自主功能所必需的。*Nagy将使用正常小鼠的生化、解剖学和超微结构方法来确定电子突触发生的位置和转基因小鼠的生理策略，以确定这些突触如何对将要检查的系统的运行做出贡献。这些结果将增加关于这些突触在神经元电路中扮演的新的、复杂的和关键的角色的新兴知识，并将作为围绕电突触的关键机械概念的翻译，使其在维持整个器官生理的运作中发挥重要作用。**