Role of Filamin A in integrin-dependent dendritic growth and hippocampus function

细丝蛋白A（Filamin A，FlnA）是一种大的二聚体蛋白质，其可以交联肌动蛋白纤维，并且充当细胞骨架和细胞膜的整合素之间的桥梁。人FLNA基因突变导致脑室周围异位，其中神经元由于迁移受损而沿侧脑室积累沿着。因此，以前的研究重点一直是FlnA对神经元迁移的重要性，其对神经元分化的贡献并不清楚。然而，我们和其他小组已经表明，肌动蛋白细胞骨架和整合素在树突的发育和可塑性中起着重要作用。在该项目的具体前期工作中，我们还收集了FlnA显著参与海马神经元树突状分支形成的证据。我们现在要调查的细胞机制，参与FlnA在树突状细胞的生长，并确定这些过程中的作用，海马依赖的信息处理和记忆formation.In该项目的第一部分，我们将研究在海马细胞培养和野生型小鼠海马发育过程中的FlnA表达和磷酸化的调节。刺激丰富的环境（“丰富的环境”）的生长促进作用被特别考虑，并涉及细胞外信号（生长因子BDNF和NGF，以及整合素介导的信号）。然后，我们将研究在原代神经元培养中FlnA的磷酸化及其与整合素的相互作用的细胞内调节机制。我们将转移我们的研究结果，以测试预期的参与FlnA在树突棘的形成。我们还将使用病毒载体来研究缺乏FlnA如何影响体内海马中的树突结构和突触密度。我们将检查这种干预的功能后果电生理切片准备和关于神经网络依赖的行为，在我们最终测试如何FlnA敲低影响环境富集后这些参数的改善。

Filamin A (FlnA) is a large dimeric protein that can cross-link actin fibers and serves as a bridge between the cytoskeleton and integrins of the cell membrane. Mutations in the human FLNA gene lead to periventricular heterotopia, in which neurons accumulate along the lateral ventricles due to impaired migration. Therefore, the focus of previous research has been on the importance of FlnA for neuronal migration and its contribution to the differentiation of neurons is not well known. However, we and other groups have shown that the actin cytoskeleton and integrins play an important role in the development and plasticity of dendrites. In specific preliminary work for this project, we have also collected evidence that FlnA is significantly involved in the formation of dendritic branches in hippocampal neurons. We now want to investigate the cellular mechanisms that underlie the involvement of FlnA in dendritic growth and determine the role of these processes in hippocampus-dependent information processing and memory formation.In the first part of the project we will study the regulation of FlnA expression and phoshorylation during development in hippocampal cell cultures and in the hippocampus of wild-type mice. The growth-promoting effects of a stimulus-rich environment (“enriched environment”) are specifically taken into account and extracellular signals involved (the growth factors BDNF and NGF, as well as integrin-mediated signals) are addressed. Then we will investigate the intracellular regulatory mechanisms for the phosphorylation of FlnA and its interaction with integrins in primary neuronal cultures. We will transfer our findings to test the expected involvement of FlnA in the formation of dendritic spines. We will also use viral vectors to investigate how the lack of FlnA affects the dendritic architecture and synapse density in the hippocampus in vivo. We will examine the functional consequences of this intervention electrophysiologically in slice preparations and with regard to hippocampus-dependent behavior, before we finally test how the FlnA knock down affects the improvement of these parameters after environmental enrichment.