EDU-GLIA · Innovative Techniques and Models to Study Glia-Neuron Interactions

Innovative Techniques and Models to Study Glia-Neuron Interactions

PROJECT OBJECTIVES The Initial Training Network Edu-GLIA included studies on a wide variety of glial cell types in various distinct neuronal networks, in order to reveal novel insights into glia-neuron interactions from early development to old age, with an emphasis on pathology and clinical impact. Each Edu-GLIA project aimed at elucidating one particular glia-neuron interaction within the central or peripheral nervous system and was assigned to one of the following three approaches: Approach A: Glial contribution to information processing Approach B: Role of glia in neurodegeneration and -regeneration Approach C: Glial progenitor cells ________________________________________________________________ MAIN RESULTS ACHIEVED In all projects, dedicated and enthusiastic young researchers could be hired, such that the scientific work was performed well, and in fact – as explicitly declared in the proposal – a new generation of future leaders in glial cell research was trained. In particular, the intended collaborations worked successfully, within the three approaches as well as in the entire network. This is exemplified by the shared use of animal models (e.g., provided by partners #13 and #7) and techniques (e.g., provided by partner #11) and by the publication of many joint articles; a few examples are • Forostyak, Romanyuk, Verkhratsky, Sykova, Dayanithi (2013) Stem Cells and Development 22: 1506-21 (partners # 8 & 9) • Reichenbach, Derouiche, & Kirchhoff (2010) Brain Res. Rev. 63: 11-25 (partners # 5 & 10) • Lu, Iandiev, Hollborn, Körber, Ulbricht, Hirrlinger, Pannicke, Wei, Bringmann, Wolburg, Wilhelmsson, Pekny, Wiedemann, Reichenbach, Käs (2011) FASEB J, 25: 624-631 (partners # 1, 7 & 10) • Parpura, Heneka, Montana, Oliet, Schousboe, Haydon, Stout Jr , Spray, Reichenbach, Pannicke, Pekny, Pekna, Zorec, Verkhratsky (2012) J. Neurochem. 121: 4-27 (partners # 6, 7, 9, 10 & 11) In approach A, research work was focused upon the characterization of transmitter receptors in white matter (optic nerve) glia (partner #2) and in brain astrocytes (partner #9), on the glial control of perisynaptic transmitter availability (partner #6) and on the release mechanisms of gliotransmitters (partner #11). It was shown that optic nerve glia expresses several types of metabotropic glutamate receptors in addition to purinergic receptors, and that glutamate signalling exerts a modulatory effect on calcium responses triggered by purinergic stimulation (partner #2). A similar interaction between glutamatergic (NMDA) und purinergic (P2Y1) receptors was elucidated in brain astrocytes by partner #9; for this purpose, a novel transgenic mouse was generated. A novel method to study the motility of (transmitter-containing) vesicles in cultured astrocytes has been established by partner #11. This method was used to demonstrate that the expression level of intermediate filaments modifies the motility of vesicles (collaboration with partner #7). Using the methodical repertoire of partner #11, partner #6 found out that the membrane diffusion of the glial glutamate transporter GLT-1 (a key molecule in control of synaptic transmitter availability) is modified by neuronal activity. Approach B has integrated work on the impact of expressing tight junction vs. aquaporin molecules in glial cell membranes on their capability to support neuronal regeneration (partner #1a), on the effects of peripheral (satellite) glial cell coupling on the development of neuropathic pain (partner #4), on the fate of glial cells invading local CNS lesions (partner #13), on the impact of intermediate filaments on biomechanical and stem cell properties of glial cells (partner #7), and on the role of biomechanics on normal and reactive glial cell functions (partner #10). Considerable methodical achievements were required – and obtained – in the projects of approach B; a novel in vitro test assay was developed by partner #1a, in vivo brain imaging was applied to novel transgenic mice by partner #13, novel molecular analysis methods were developed by partner #7 (in collaboration with partner # 12), and innovative organotypic culture substrates (patent implemented) and a novel experimental setup for mechanical stress application were generated by partner #10. In addition, partner #4 has shown that pharmacological block of glial cell coupling may become a promising therapeutic approach in neuropathic brain. Approach C was focused upon the potential use of glial cells as stem cells for neurorepair. Partner #3 studied the key regulator molecules of glia-derived adult neural stem cells; partner #12 developed reliable and versatile methods to study the single-cell expression profiling of astrocytic progenitor cells; the work of partner #8 was devoted to the acceleration of neuronal differentiation of glia-derived stem cells; and partner #1b searched for molecules mediating the neuroprotective capacity of glial cells in retinal injuries. Important results of these studies were the detection of a key regulatory molecule, Dlx4, in adult neuronal stem cells (partner #3) and of a highly potent neurotrophic factor, osteopontin, in retinal glial cells (partner #1b). Partner #8 and #12 developed novel methods, which were (and also will be in future) used by other partners of the network. In summary, the projects of the network successfully advanced towards the final aim, viz. the delivery of novel knowledge, tools, and approaches to use (modulations of) glial cells in innovative therapies of neurological diseases. All of the fellows in the projects will achieve their PhD in due time, and many of them already got postdoc positions in (partnering) groups of Edu-GLIA, or in oversea labs (mediated by the partners of the network). ________________________________________________________________ PROJECT WEBSITE: www.eduglia.eu ________________________________________________________________ CONTACT Project Management: Dr. Thomas Wheeler-Schilling Dr. Sigrid Diether Eberhard-Karls-Universität Tübingen Centre for Ophthalmology, Research Management Unit Frondsbergstrasse 23 D - 72070 Tübingen, Germany Email: thomas.wheeler-schilling@uni-tuebingen.de sigrid.diether@uak-swm.de Research Coordinator: Prof. Dr. Andreas Reichenbach Universität Leipzig, Medical Faculty Paul-Flechsig-Institute for Brain Research Jahnallee 59 D - 04109 Leipzig, Germany Email: reia@medizin.uni-leipzig.de

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