Plasticity of Mammalian Electrical Synapses

描述(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。尽管有压倒性的证据表明它们的重要性和广泛的分布，但人们仍然对它们进行整形的能力知之甚少。哺乳动物的电子突触可以像化学突触一样动态和可修改的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Mauthner细胞上可识别的混合突触上的电突触受其共定位的谷氨酸能突触的调节，其活性通过NMDA受体的激活而诱导电传递的长期增强。最近的数据表明，这些终末的电传递是由连接蛋白35介导的，连接蛋白35是哺乳动物神经元连接蛋白36的FISH同源基因。间隙连接蛋白36的广泛分布和所提出的调控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控。我们建议在大鼠的电突触上测试这一预测，特别是在下橄榄的那些突触上，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验证下橄榄细胞间电突触受相邻谷氨酸能突触活动调控的假说。这是基于初步的超微结构研究表明，与金鱼混合突触一样，连接蛋白36标记的缝隙连接与NMDA受体标记的突触后密度非常接近，足以使信号分子在两种类型的结构之间扩散。目的2是研究电传递活动依赖变化的机制。我们会问，这些机制的要求是否类似于对Mauthner细胞突触的要求(涉及CaM-KII的NMDA受体激活)，或者，或者，涉及不同的信号通路。这项拟议的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改变的。这一特性可能广泛存在，并与癫痫和发育障碍等病理情况有关。这项应用探索了化学介导的突触调节缝隙连接介导的电突触功能的可能性。突触是哺乳动物大脑中神经元间交流的主要形式。由于电突触已被证明可以促进神经元的协调活动，这种调节的存在可能会产生深远的生理和病理影响，导致癫痫以及认知(精神)和发育障碍。

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.