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）：过去几年标志着电气突触研究的文艺复兴，已显示出在整个哺乳动物大脑的越来越多的区域中存在。尽管有大量的证据表明其重要性和广泛的分布，但对他们经历塑料变化的能力仍然知之甚少。哺乳动物电突触可以像化学突触一样动态和修改的观念可以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的电气突触受其共定位的谷氨酸能突触的调节，其活性通过NMDA受体激活诱导电气传播的长期增强。最近的数据表明，这些末端的电气传输是由哺乳动物神经元连接的鱼类直系同源物的Connexin35介导的。 connexin36的广泛分布和所提出的调节元件的普遍性表明哺乳动物电突触可以类似地调节。我们建议在大鼠的电突触中测试这一预测，尤其是在下橄榄的那些预测，其中超微结构和生理特征似乎有利于这种可能性。 AIM 1检验了以下假设：下橄榄细胞之间的电突触受到邻近谷氨酸能突触的活性调节。它基于初步超微结构研究，表明，与金鱼混合突触中一样，标记为连接的链接连接处与NMDA受体标记的突触后密度相近，足以在两种结构之间扩散信号分子的扩散。目标2是研究电动传输中活性依赖性变化的机制。我们将询问机械要求是否类似于Mauthner细胞突触（涉及CAM-KII的NMDA受体激活）或涉及不同信号通路的机械需求。拟议的研究解决了一个新的概念，即哺乳动物电突触的强度通过附近化学突触的活性动态地改变。该特性可能广泛地与病理状况有关，例如癫痫和发育障碍。该应用程序探讨了化学介导的突触（哺乳动物大脑中神经元通信的主要形式）调节间隙连接介导的电气突触的功能的可能性。由于电气突触已被证明促进了协调的神经元活性，因此这种调节的存在可能具有深远的生理和病理意义，有助于癫痫和认知（精神病）和发育障碍。