Regulation of Retinal Gap Junctions

 描述(申请人提供)：整个中枢神经系统的神经元使用化学和电突触来形成突触连接的网络。这两种形式的突触都通过各种机制受到可塑性的影响，这种可塑性是感觉信号处理、行为和学习过程中电路优化的基本基础。在视网膜内，由缝隙连接形成的电突触对信号有贡献 大多数类型神经元的处理功能。电突触可塑性是一个标志性特征 视觉适应，对许多神经元的敏感性和感受场特性有深远的影响，并影响哺乳动物视杆细胞通路中的信号流路径。这项研究的长期目标是确定调节视网膜中电突触的机制，并确定哪些调节模式对在不同的电耦合神经回路中观察到的适应过程最重要。我们早期的工作表明，改变连接蛋白36(Cx36)缝隙连接磷酸化状态的信号机制可以改变偶联程度超过一个数量级，并在光适应下动态地做到这一点。显然，控制不同电耦合神经网络的机制各不相同，但某些主题在整个中枢神经系统中反复出现。Cx36的CaM-Kinase磷酸化在钙信号转导中的重要作用就是这样一个主题。在这个项目中，我们将研究在电突触中介导钙信号的分子机制。我们将研究钙信号是如何通过NMDA型谷氨酸受体传递到缝隙连接的，并研究钙调蛋白与连接蛋白结合所起的作用。我们将用一个遗传编码的钙传感器来检测视网膜中电子突触上钙信号的盛行程度。最后，我们将研究分子支架是如何形成复合体的，这些复合体整合了电子突触上的不同调控信号。这项研究的结果将有助于设计有针对性的干预措施来操纵缝隙连接耦合。这种干预措施在视网膜缺血或中枢神经系统其他部分发生的类似事件中可能有用，在这些事件中，神经元缝隙连接耦合加剧了损伤。

 DESCRIPTION (provided by applicant): Neurons throughout the central nervous system employ both chemical and electrical synapses to form synaptically connected networks. Both forms of synapse are subject to plasticity through a variety of mechanisms, and such plasticity is a fundamental substrate for circuit optimization during sensory signal processing, behavior, and learning. Within the retina, electrical synapses, formed by gap junctions, contribute to the signal processing functions of most types of neurons. Electrical synaptic plasticity is a hallmark feature of visual adaptation, having profound effects on the sensitivity and receptive field properties of many neurons and influencing the path of signal flow in the mammalian rod pathway. The long-term objectives of this study are to identify the mechanisms that regulate electrical synapses in the retina and to determine which modes of regulation are most important for the adaptive processes observed in different electrically coupled neural circuits. Our earlier work has shown that signaling mechanisms that change the phosphorylation state of connexin 36 (Cx36) gap junctions can change the degree of coupling by more than an order of magnitude and do so dynamically with light adaptation. It is apparent that the mechanisms that control different electrically coupled neural networks vary, but certain themes recur throughout the central nervous system. An important role for calcium signaling via CaM Kinase phosphorylation of Cx36 is one such theme. In this project, we will examine the molecular mechanisms that mediate calcium signaling at electrical synapses. We will examine how calcium signals are delivered to the gap junctions via NMDA-type glutamate receptors and examine the role played by calmodulin binding to the connexin. We will examine the prevalence of calcium signaling at electrical synapses in the retina with a genetically encoded calcium sensor. Finally, we will investigate how molecular scaffolds form complexes that integrate different regulatory signals at electrical synapses. The results of this study will be useful to design targeted interventions to manipulate gap junctional coupling. Such interventions could be useful in incidents of retinal ischemia or similar events in other parts of the central nervous system in which neuronal gap junctional coupling exacerbates injury.