Modulation of synaptic transmission by a novel activity-dependent regulatory mechanism of astrocytic gap junction coupling

通过星形细胞间隙连接耦合的新型活性依赖性调节机制调节突触传递

• 批准号: 5430344
• 负责人: Professor Dr. Swen Hülsmann
• 金额: --
• 依托单位: Klinik für Anästhesiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2004
• 资助国家: 德国
• 起止时间: 2003-12-31 至 2008-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5430344?language=en
• 关键词: Modulation; synaptic; transmission; novel; activity

It is known that gap junction coupling between astrocytes is regulated by neuronal activity. Such modification of gap junction coupling will modify the operation of synapses by different processes, such as modulation of spatial buffering, transmitter up-take, and release of modulatory factors. Recently, we were able to show that the interaction of drebrin with connexin 43 (Cx43) stabilizes gap junction coupling in astrocytes. As demonstrated in neurons, drebrin might also serve as a signal transduction mechanism in astrocytes, which signals to other components of the sub-membrane cytoskeleton as well as to Cx43. This might be responsible for regulation of cell-cell coupling. It remains to be investigated, however, how drebrin-mediated changes of Cx43-function and gap junction coupling in astrocytes modulate on-going synaptic activity. The proposed project is aiming to analyze the functional significance of the activity-dependent regulation of synaptic transmission. In the new DFG program we will aim to prove the following hypothesis. (1) Neuronal activity modulates coupling of adjacent astrocytes by modifying Drebrin-Cx43 interaction. (2) This Drebrin-Cx43 interaction provides a novel activitydependent mechanism for sensing and adjusting synaptic transmission. To answer these questions, we will use different experimental model systems, including cell culture, in which transfection of siRNA against drebrin allows specific down-regulation of cellcell communication in astrocytes and parallel electrophysiological analysis of synaptic activity. Additionally, this novel interaction will be analyzed in acute brain slices, in which we will inject siRNA into a population of identified astrocytes from Tgn(GFAP-EGFP) mice. This will allow us to investigate the Drebrin-Cx43 mediated modulation of synaptic transmission in a functional environment.

已知星形胶质细胞之间的缝隙连接偶联受神经元活动的调节。这种缝隙连接耦合的改变将通过不同的过程来改变突触的操作，如空间缓冲的调制、递质摄取和调制因子的释放。最近，我们发现Drebrin与连接蛋白43(Cx43)的相互作用稳定了星形胶质细胞的缝隙连接偶联。正如在神经元中证明的那样，Drebrin也可能作为星形胶质细胞的信号转导机制，向亚膜细胞骨架的其他组件以及Cx43发出信号。这可能与细胞-细胞耦合的调节有关。然而，Drebrin介导的Cx43功能改变和星形胶质细胞缝隙连接偶联如何调节正在进行的突触活动仍有待研究。该项目旨在分析突触传递的活性依赖调节的功能意义。在新的DFG程序中，我们将致力于证明以下假设。(1)神经元活动通过改变Drebrin-Cx43相互作用来调节相邻星形胶质细胞之间的偶联。(2)这种Drebrin-Cx43相互作用为感觉和调节突触传递提供了一种新的活动依赖机制。为了回答这些问题，我们将使用不同的实验模型系统，包括细胞培养，在这种系统中，针对Drebrin的siRNA转基因可以特异性地下调星形胶质细胞中的细胞通讯，并对突触活动进行平行的电生理学分析。此外，这种新的相互作用将在急性脑切片中进行分析，在其中我们将向TGN(GFAP-EGFP)小鼠的一组已识别的星形胶质细胞注入siRNA。这将使我们能够在功能环境中研究Drebrin-Cx43介导的突触传递的调制。