The role of electrical synaptic plasticity in retinal function

项目摘要 中枢神经系统的神经元通过各种突触组成网络 互动。由神经元之间的缝隙连接形成的电突触是这一结构的核心组成部分 组织。电突触可以同步同一类型神经元网络的活动，并为 不同类型神经元之间的快速、双向电通信。这些属性非常重要 中枢神经系统的许多高阶网络功能。 电突触不是一成不变的，而是受到严格调控的。连接蛋白磷酸化状态的变化 在一些视网膜神经元中，36(Cx36)修饰偶联的数量超过一个数量级 动态范围。这种耦合的变化是视网膜光适应的一个刻板印象的因素，而且许多 电耦合视网膜网络在白天保持非常差的耦合状态，以优化其 功能。贯穿中枢神经系统的绝大多数电性突触由 Cx36。所有这些突触都具有相同的可塑性，但对 大多数网络或其功能状态的可塑性。 这个项目探索了一个假设，即电耦合网络的最优功能通常是最好的 由弱耦合服务的。为了验证这一假设，我们将开发条件突变小鼠，在这些小鼠中 通过模拟Cx36磷酸化的点突变，电突触被锁定在开放状态。这 应该会在大多数受影响的网络中造成异常高的耦合。这些动物将被用来确定 白天视网膜神经网络的强耦合对视觉功能和行为的影响。 进一步的研究将具体检查使用电突触可塑性来重新配置视杆的必要性。 白天的视觉通路，以优化明视光线下的神经节细胞反应。这个动物模型将是 对研究中枢神经系统中大多数其他回路中电耦合的可塑性很有用。它将会有 进一步研究缝隙连接偶联在脑损伤和脑损伤中旁观者细胞死亡中的作用 疾病。

Project Summary Neurons of the central nervous system are organized into networks through a variety of synaptic interactions. Electrical synapses, formed by gap junctions between neurons, are a core component of this organization. Electrical synapses can synchronize activity of networks of the same neuron type and provide rapid, bi-directional electrical communication between neurons of different type. These properties are critical for many high-order network functions of the central nervous system. Electrical synapses are not static, but are tightly regulated. Changes in phosphorylation state of connexin 36 (Cx36) in some retinal neurons modify coupling quantitatively over more than an order of magnitude dynamic range. Such changes in coupling are a stereotyped element of retinal light adaptation, and many electrically coupled retinal networks are held in a very poorly coupled state during the daytime to optimize their function. The vast majority of electrical synapses throughout the central nervous system are composed of Cx36. ALL of these synapses are capable of the same scale of plasticity, but very little is known about the plasticity of most networks or their functional state. This project explores the hypothesis that optimal function of electrically coupled networks is often best served by weak coupling. To test this hypothesis we will develop conditional mutant mice in which the electrical synapses are locked in an open state by point mutations that mimic phosphorylation of Cx36. This should cause unusually high coupling in most networks affected. These animals will be used to determine the impact of strong coupling of neural networks in the retina in the daytime on visual functions and behavior. Further studies will examine specifically the necessity to use electrical synaptic plasticity to reconfigure rod visual pathways in the daytime to optimize ganglion cell responses in photopic light. This animal model will be useful to study plasticity of electrical coupling in most other circuits in the central nervous system. It will have further utility in studies of the role of gap junctional coupling in bystander cell death in brain injuries and diseases.