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

• Applicant: Professor Dr. Oliver Stork
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 463265570

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.

• DFG Programme: Research Grants