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，已经证明电突触存在于哺乳动物大脑中越来越多的区域中。尽管有压倒性的证据表明它们的重要性和广泛分布，但人们对它们发生塑性变化的能力仍然知之甚少。哺乳动物的电突触可以像化学突触一样具有动态性和可变性，这一概念可能会极大地改变我们对它们的性质和功能相关性的看法。金鱼Mauthner细胞上可识别的混合突触接触处的电突触受其共同定位的NMDA能突触的调节，其活性通过NMDA受体激活诱导电传递的长时程增强。最近的数据表明，在这些终端的电传输介导的连接蛋白35，鱼类直系同源的哺乳动物神经元连接蛋白36。连接蛋白36的广泛分布和普遍存在的建议的调节元件表明，哺乳动物的电突触可能受到类似的调节。我们建议在大鼠的电突触中测试这一预测，特别是在那些下橄榄，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相邻的突触活动调节的假说。它是基于初步的超微结构研究表明，在金鱼混合突触，间隙连接标记为connexin 36是在接近标记为NMDA受体的突触后密度，足够接近的信号分子之间的扩散两种类型的结构。目的2是研究电传递中活动依赖性变化的机制。我们将询问是否机制要求与Mauthner细胞突触（涉及CaM-KII的NMDA受体激活）相似，或者涉及不同的信号通路。这项研究提出了一个新的概念，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。这种性质可能是广泛的，并与病理条件，如癫痫和发育障碍。该应用程序探讨了化学介导的突触，在哺乳动物大脑中的神经元间通信的主要形式，调节间隙连接介导的电突触的功能的可能性。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刻的生理和病理意义，有助于癫痫和认知（精神）和发育障碍。