Indrek Koppel

The nervous system consists of multiple cell types with distinct physiological specializations and gene expression patterns. In tissue, these cells form a complex, intertwined network that is subject to constant interaction between different cell types. This complexity poses a challenge for researchers in both separating cell types for analysis as well as studying interactions and information transfer between cells. In this application, we propose a molecular neuroscience study addressing both aspects. First, we are developing proteomics methods to allow analysis of newly synthesized proteins on a cell type-specific basis. Second, we shall use novel genetic tools for cell type-specific stimulation and gene expression analysis in primary co-cultures of neurons and astroglial cells. We shall use this system to probe gene expression signatures in neuron-astrocyte communication and determine the transmitters that form the basis of this communication.

Astrocytes comprise one of the main cell types in the central nervous system (CNS), and it is now recognized that they have important roles in ensuring proper development and homeostasis of the CNS, with astrocyte dysfunction contributing to all major neurological disorders. Recent studies have shown that these cells undergo dramatic transcriptional changes in response to neuron-derived stimuli. However, what are the astrocyte-specific mechanisms that regulate these changes are still largely unknown. Here, this issue will be tackled using state-of-the art functional genomic approaches to generate a comprehensive map of the astrocyte-specific regulatory elements (with a focus on enhancers) and transcription factors that govern stimuli-induced gene expression changes. This will provide unique and original insights into the mechanisms that control stimuli-induced gene expression in non-neuronal CNS cells, with potential implications for the understanding of several neuropathologies.

This project took a closer look at how BDNF, an important protein usually studied in neurons, is regulated in heart cells and in special brain cells called astrocytes. First, we figured out signals that “switch on” BDNF, such as noradrenaline (similar to adrenaline), and studied DNA regions that help controlling this switch, specifically in cardiac cells. We then focused on astrocytes, a kind of brain cell that supports neurons, among other functions. We observed that when neurons and astrocytes are maintained together and neurons are activated, astrocytes respond by producing more BDNF. BDNF is an actively studied protein, given its critical roles in the central nervous system and especially in neurons. More recently, BDNF expression and function have been studied in other cell types as well, revealing a larger spectrum of roles for this neurotrophin. Furthermore, its dysregulation in several pathological conditions make it an interesting target for therapeutic interventions. The results obtained in the frame of this project are therefore interesting to the neurotrophin community, and more broadly to the neurobiology and cardiac biology fields, and provide the fundamental knowledge required to design and implement treatment strategies. Different methodologies needed to be put in place an optimized in order to achieve the goals of this project. As a result, these are now part of the group’s diverse tool kit and can be implemented to address several of our research questions, which I find to be an important outcome of the project. Finally, the successful defence of the MSc thesis of a co-supervised student is an important milestone and a key achievement associated with this grant.