Neuron-glia interactions and extracellular matrix post-stroke

Egor Dzyubenko studied biology, biophysics and bionanotechnology at Lomonosov’s Moscow State University and received his diploma in 2011. His diploma thesis focussed on the dynamics of mitochondrial membrane potential during hyperglycaemic stress in cultivated neurons. He performed his PhD thesis at the Department of Cell Morphology and Molecular Neurobiology of the Ruhr University Bochum under the supervision of Prof. Dr. Andreas Faissner from 2012 until 2016. His thesis entitled ‘Modifying synaptogenesis and functional state of neural networks in vitro: insights from antipsychotic treatments and extracellular matrix depletion’ was awarded with the grade “with distinction”. Subsequently, he moved to the University Hospital Essen and joined the NeuroScienceLab within the Chair of Vascular Neurology, Dementia and Ageing Research in 2017.

Human brain is comprised out of around 100 billion of neurons, interconnected by a quadrillion of synapses, and around a trillion of glial cells. The stable functioning of this enormously complex organ relies on multiple regulatory mechanisms, many of which involve extracellular matrix (ECM) and neuron-glia interactions. Hence, his research on the three main questions:

• What is the role of astrocytes, ECM and peri-neuronal nets for neuronal plasticity and neuronal network function?
• Can we modify neuronal networks exogenously, and how can patients with neurological diseases benefit from it?
• Which are the molecular signals that lead to neurological recovery?

To address these challenging tasks, he combines animal models and cell culture techniques, bridging structural histochemical and electrophysiological methods (e.g., Multi Electrode Arrays, MEA). Within his studies, he establishes cutting-edge superresolution imaging tools (STED, SIM, PALM) and evaluates neuronal connectivity by computational approaches.

Dzyubenko E, Juckel G and Faissner A. Antipsychotic drugs olanzapine and haloperidol modify network connectivity and spontaneous activity of neural networks in vitro. Sci Rep., under revision

Gottschling C, Dzyubenko E, Geissler M, Faissner A. The indirect neuron-astrocyte coculture assay: An in vitro set-up for the detailed investigation of neuron-glia interactions. J Vis Exp. 2016; 117. 

Dzyubenko E, Rozenberg A, Hermann DM, Faissner A. Colocalization of synapse marker proteins evaluated by STED-microscopy reveals patterns of neuronal synapse distribution in vitro. J Neurosci Meth. 2016; 273: 149-159.

Dzyubenko E, Gottschling C, Faissner A. Neuron-Glia Interactions in neural plasticity: Contributions of neural extracellular matrix and perineuronal nets. Neural Plast. 2016; 2016: 5214961.

Efremov Y, Dzyubenko E, Bagrov D, Maksimov G, Shram S, Shaitan K. Atomic force microscopy study of the arrangement and mechanical properties of astrocytic cytoskeleton in growth medium. Acta Naturae. 2011; 3(3):93-9. 

Matthias Pilath-Eilers studied biology at the Heinrich Heine University Düsseldorf and received his Bachelors degree in 2018 for a thesis investigating changes in extracellular potassium homeostasis evoked by Gamma aminobutyric acid in mouse hippocampus. Matthias finished his master degree 2021. He conducted his thesis at the NeuroScienceLab, investigating the effect of interleukin activated microglia on synapses of primary neuron-astrocyte co-cultures as well as live cell imaging of GCaMP6f astrocytes to study the effect of activated microglia on astrocytic calcium signalling.

Ischemic stroke not only affects the blood-brain barrier and astrocytes but also alters the integrity of extracellular matrix (ECM). Changes in ECM reach from rearrangements after mild hypoperfusion to degradation after focal cerebral ischaemia and are closely related to reactive astrocytes. It is expected that the interplay between ECM and astrocytes is important for the formation of new synapses, yet the question how astrocytes detect changes in the ECM remains open. Potentially, the ECM-astrocyte interaction is mediated by mechanoreceptors, but their role in post stroke brain remodelling remains unknown.

Britta Kaltwasser completed her education as a Biology Lab Assistant at the University of Göttingen in 1994. Her professional activities as research technician started at the Institute of Humangenetics in Göttingen, followed by trainings and stays in research & development units of biomedical companies. Britta Kaltwasser gathered first experience in stroke research at the Department for Neurology of the University Hospital Göttingen. She then joined the Chair of Vascular Neurology, Dementia and Ageing Research and NeuroScienceLab in November 2010. 

Techniques and methods used by Britta Kaltwasser include, but are not restricted to cell and stem cell culture, immunohistochemistry, Western blotting, ELISA and PCR.

Doeppner TR, Kaltwasser B, Sanchez-Mendoza EH, Caglayan AB, Bähr M, Hermann DM. Lithium-induced neuroprotection in stroke involves increased miR-124 expression, reduced RE1-silencing transcription factor abundance and decreased protein deubiquitination by GSK3β inhibition-independent pathways. J Cereb Blood Flow Metab. 2017; 37(3):914-926. 

Hermann DM, Zechariah A, Kaltwasser B, Bosche B, Caglayan AB, Kilic E, Doeppner TR. Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia. Neurobiol Dis. 2015; 83:16-25. 

Doeppner TR, Pehlke JR, Kaltwasser B, Schlechter J, Kilic E, Bähr M, Hermann DM. The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration. J Cereb Blood Flow Metab. 2015; 35(12):2089-97. 

Doeppner TR, Kaltwasser B, Fengyan J, Hermann DM, Bähr M. TAT-Hsp70 induces neuroprotection against stroke via anti-inflammatory actions providing appropriate cellular microenvironment for transplantation of neural precursor cells. J Cereb Blood Flow Metab. 2013; 33(11):1778-88. 

Doeppner TR, Doehring M, Bretschneider E, Zechariah A, Kaltwasser B, Müller B, Koch JC, Bähr M, Hermann DM, Michel U. MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation Acta Neuropathol. 2013; 126(2):251-65. 

Doeppner TR, Mlynarczuk-Bialy I, Kuckelkorn U, Kaltwasser B, Herz J, Hasan MR, Hermann DM, Bähr M. The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis Brain. 2012; 135(Pt 11):3282-97. 

Doeppner TR, Kaltwasser B, ElAli A, Zechariah A, Hermann DM, Bähr M. Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation. J Cereb Blood Flow Metab. 2011; 31(5):1251-62.