Plasticity of Mammalian Electrical Synapses

哺乳动物电突触的可塑性

• 批准号: 7469564
• 负责人: Alberto E Pereda
• 金额: $ 18.16万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469564
• 关键词: Address; Area; Auditory; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Cells; Characteristics; Chemical Synapse; Chemicals; Chromosome Pairing; Cognitive; Communication; Condition; Connexins; Coupling; Data; Diffusion; Electrical Synapse; Enzyme Activation; Epilepsy; Fiber; Fishes; Freeze Fracturing; Gap Junctions; Glutamate Receptor; Glutamates; Goldfish; Human; Imaging Device; Inferior; Label; Localized; Long-Term Potentiation; M cell; Mammals; Mediating; Midbrain structure; Modality; Modification; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neurons; Numbers; Olives - dietary; Orthologous Gene; Perception; Physiological; Plastics; Preparation; Property; Purpose; Rattus; Reagent; Receptor Activation; Regulation; Regulatory Element; Renaissance; Research; Risk; Signal Pathway; Signal Transduction; Signaling Molecule; Slice; Structure; Study models; Synapses; Testing; Vertebrates; Whole-Cell Recordings; base; cell type; concept; connexin 36; density; developmental disease; human NR1 protein; novel; postsynaptic; transmission process

DESCRIPTION (provided by applicant): The past few years marks a renaissance in the study of electrical synapses which have been shown to exist in an ever-increasing number of areas across the mammalian brain. Despite the overwhelming evidence for their importance and widespread distribution, still little is known about their ability to undergo plastic changes. The notion that mammalian electrical synapses could be as dynamic and modifiable as chemical synapses could dramatically change our perception about their properties and functional relevance. Electrical synapses at identifiable mixed synaptic contacts on goldfish Mauthner cells are regulated by their co-localized glutamatergic synapses, whose activity induces long-term potentiation of electrical transmission via NMDA receptor activation. Recent data show that electrical transmission at these terminals is mediated by connexin35, the fish ortholog of the mammalian neuronal connexin36. The widespread distribution of connexin36 and the ubiquity of the proposed regulatory elements suggest that mammalian electrical synapses may be similarly regulated. We propose to test this prediction at electrical synapses in the rat, in particular at those of the Inferior Olive, where ultrastructural and physiological features appear to favor such possibility. Aim 1 tests the hypothesis that electrical synapses between inferior olivary cells are regulated by the activity of neighboring glutamatergic synapses. It is based on preliminary ultrastructural studies suggesting that, as in goldfish mixed synapses, gap junctions labeled for connexin36 are in close proximity to postsynaptic densities labeled for NMDA receptors, sufficiently close for diffusion of signaling molecules between the two types of structures. Aim 2 is to investigate the mechanisms underlying activity-dependent changes in electrical transmission. We will ask if the mechanistic requirements are similar to those found for Mauthner cell synapses (involving NMDA receptor activation of CaM-KII) or, alternatively, different signaling pathways are involved. The proposed research addresses the novel concept that the strength of mammalian electrical synapses is dynamically modified by the activity of nearby chemical synapses. This property could be widespread and relevant to pathological conditions such as epilepsy and developmental disorders. The application explores the possibility that chemically mediated synapses, the main form of interneuronal communication in the mammalian brain, regulate the function of gap junction-mediated electrical synapses. Because electrical synapses have been shown to promote coordinated neuronal activity, the existence of such regulation could have profound physiological and pathological implications, contributing to epilepsy and to cognitive (psychiatric) and developmental disorders.

描述（由申请人提供）：过去几年标志着电突触研究的复兴，电突触已被证明存在于哺乳动物大脑中越来越多的区域。尽管有大量证据表明它们的重要性和广泛分布，但人们对它们经历可塑性变化的能力知之甚少。哺乳动物的电突触可以像化学突触一样动态和可修改，这一概念可能会极大地改变我们对它们的特性和功能相关性的看法。金鱼毛纳细胞可识别的混合突触接触处的电突触受其共定位的谷氨酸能突触调节，其活性通过NMDA受体激活诱导电传递的长期增强。最近的数据表明，这些末端的电传输是由连接蛋白介导的，连接蛋白是哺乳动物神经元连接蛋白的鱼类同源物。connexin36的广泛分布和所提出的调节元件的普遍存在表明，哺乳动物的电突触可能也受到类似的调节。我们建议在大鼠的电突触上测试这一预测，特别是下橄榄的电突触，那里的超微结构和生理特征似乎有利于这种可能性。目的1验证下橄榄细胞间的电突触受邻近谷氨酸突触活动调节的假说。这是基于初步的超微结构研究，表明在金鱼混合突触中，标记为connexin36的间隙连接与标记为NMDA受体的突触后密度非常接近，足够接近信号分子在两种结构之间的扩散。目的2是研究电传输中活动依赖性变化的机制。我们将询问其机制要求是否与Mauthner细胞突触相似（涉及CaM-KII的NMDA受体激活），或者是否涉及不同的信号通路。提出的研究解决了一个新概念，即哺乳动物电突触的强度是由附近化学突触的活动动态修改的。这种特性可能是广泛的，并与病理条件有关，如癫痫和发育障碍。该应用程序探索了化学介导的突触（哺乳动物大脑中神经元间通信的主要形式）调节间隙连接介导的电突触功能的可能性。由于电突触已被证明可以促进协调的神经元活动，这种调节的存在可能具有深远的生理和病理意义，有助于癫痫、认知（精神）和发育障碍。