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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612620
• 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.

间隙连接是由连接蛋白形成的细胞间通讯通道的聚集体，连接蛋白在全身细胞中发挥着重要作用。当神经元之间出现间隙连接时，它们会产生电突触，介导神经元之间的直接电通信。纳吉的团队和其他人揭示了哺乳动物大脑和脊髓的许多区域中电突触的普遍性和重要性。他的研究计划集中在两个长期目标：i）破译电突触的结构和调节蛋白成分； ii) 了解这些突触在神经元回路中的功能作用。关于后一个目标的拟议工作旨在提供对三个不同神经元系统中电突触的发生和要求的基本了解，每个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新的功能特性，并提供必要的同步机制，这些同步机制对于每个系统中的神经元活动以及这些系统所维护的功能至关重要。 要检查的三个系统包括： i) 初级传入无髓鞘感觉 C 纤维，具有许多重要功能，包括调节生理上关键的外周轴突反射。据报道，这些光纤在几十年前就已实现电耦合，但这种耦合的基础仍然未知。 Nagy 最近发现了感觉神经元中存在间隙连接形成蛋白 connexin36 的证据，并旨在确定 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) 脊髓中的性二态运动神经元，控制膀胱排空和性活动，Nagy 的研究小组最近在其中发现了大量由连接蛋白 36 形成的电突触； iii) 脊髓中的节前交感神经元，已知其中存在电突触，但对这些突触的组织或其功能作用一无所知，需要了解这些知识才能更全面地了解交感神经元如何控制一系列自主功能。 纳吉将在正常小鼠中使用生化、解剖和超微结构方法来识别电突触发生的部位，并在转基因小鼠中使用生理策略来确定这些突触如何促进待检查系统的运行。研究结果将增加人们对这些突触在神经元回路中所发挥的新颖、复杂和关键作用的认识，并将作为围绕电突触的关键机械概念的翻译，解释它们在维持整个器官生理学运作中的重要性。