Modulation of signal transmission in the hippocampus by GluR-type astroglial cells
Zusammenfassung der Projektergebnisse
Neurons of the brain signal to each other through contact sites called synapses. It is the activity of this complex neuronal network in our brains which makes us think, decide, learn and remember. Until a decade ago, neurons were thought to exclusively mediate information processing, even though the majority of cells in the brain are not neurons, but glial cells. Recent work on neuroglial cell physiology showed these cells are much more actively involved in brain information processing than previously anticipated. This finding has stimulated the novel view that the brain should no longer be regarded solely as a neuronal network, but instead as a circuit of interactive neuron and glial cell networks. In particular, astrocytes are in very close contact to synapses. In fact, they can sense and respond to neuronal activity and thereby control the way neurons talk to each other via their synapses. In our project, we have investigated the impact of two different types of neuroglial cells, astrocytes and NG2 cells, on neuronal activity in the brain. A main finding is the insight that astrocytes considerably differ in their functional properties. We could unexpectedly show that astrocytes in the hippocampus and thalamus use different proteins to form interconnected networks (gap junctions proteins connexin43 and 30, respectively). Thus, astrocytes of different brain regions might modify neuronal signaling through distinct mechanisms. Similar to neurons, astrocytes can release transmitters in a Ca^2+-regulated manner, although underlying mechanisms are not well understood. We could now identify two members of the synaptotagmin family in hippocampal astrocytes, Syt-7 and Syt-11. In neurons, synaptotagmins are crucial members of the presynaptic transmitter release machinery, suggesting a similar function in astrocytes. Astrocytes play a key role in the control of the K+ homeostasis in the brain. We have now identified three types of channels in the astrocytes which contribute to this process: the K channels Kir4.1 and TREK, and the water channel AQP4. Proper function of these channels is a key prerequisite to avoid neuronal hyperactivity. A special type of astrocytes, the so-called radial glia (RG)-like cells, serve as stem cells to produce new neurons throughout postnatal life. We have now demonstrated that in the dentate gyms, connexin expression by RG-like cells is crucial for intact adult neurogenesis. A second type of neuroglia in the brain is NG2 cells, which receive direct synatic input from neurons. While in the white matter most NG2 cells differentiate into oligodendrocytes, the functional role of NG2 cells in grey matter is completely unknown. We could now demonstrate that in the hippocampus these cells are heterogeneous with respect to their transcript expression pattern and antigen profile. Moreover, we could identify several Ca^2+- signalling pathways in NG2 cells, and demonstrate that their processes are highly motile. Our data reveal that grey matter NG2 cells are endowed with the cellular machinery for two-way communication with neighboring cells. Our findings have been recognized by the media (e.g. Bild der Wissenschaft 9:20-26, 2008; Pressemitteilung der Uni Bonn vom 10.06.2009).
Projektbezogene Publikationen (Auswahl)
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(2008). Astrocytic function and its alteration in the epileptic brain. Epilepsia 49(S2-3): 3-12
Jabs, R., G. Seifert and C. Steinhäuser
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(2008). Astroglial mechanisms in epilepsy. In: Epilepsy. A comprehensive textbook. Second edition. Engel, J. and Pedley, T.A, (eds.), Lippincott Williams & Wilkins, 277-288
Steinhäuser, C., P. Haydon and N. de Lanerolle
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(2008). Functional analysis of ES cell-derived glial cells after integration into hippocampal slice cultures. Stem Cells Dev. 17:1141-1152
Husseini, L., T. Schmandt, B. Scheffler, W. Schröder, G. Seifert, O. Brüstle, C. Steinhäuser
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(2008). NG2-express!ng cells in the nervous system revealed by NG2-EYFP-knockin mouse. Genesis 46:743-757
Karram, K., S. Goebbels, M. Schwab, K. Jennissen, G. Seifert, C. Steinhäuser, K.-A. Nave, J. Trotter
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(2009). Analysis of astroglial K+ channel expression in the developing hippocampus reveals a predominant role of the Kir4.1 subunit. J. Neurosci. 29:7474- 7488
Seifert, G., K. Hüttmann, D. Binder, C. Hartmann, A. Wyczynski, C. Neusch, C. Steinhäuser
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(2009). Connexin expression by radial glia-like cells is required for neurogenesis in the adult dentate gyrus. Proc. Natl. Acad. Sci. USA 106:11336-11341
Kunze, A., M.R. Congreso, C. Hartmann, A. Wallraff-Beck, K. Hüttmann, P. Bedner, R. Requardt, G. Seifert, C. Redecker, K. Willecke, A. Hofmann, A. Pfeifer, M. Theis, C. Steinhäuser
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(2009). Differential mRNA patterns of synaptotagmin gene family members in the brain. J. Comp. Neurol. 512:514-518
Mittelstaedt, T., G. Seifert, E. Alvarez-Baron, C. Steinhäuser, A. Becker, S. Schoch
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(2009). Quality control of astrocytedirected Cre transgenic mice: The benefits of a direct link between loss of gene expression and reporter activation. Glia 57:680-692
Requardt R.P., L. Kaczmarczyk, P. Dublin, A. Wallraff-Beck, T. Mikeska, J. Degen, A. Waha, C. Steinhäuser, K. Willecke, M. Theis
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(2009). Role of astrocyte dysfunction in epilepsy. In: Encyclopedia of Basic Epilepsy Research 1:412-417
Binder, D. and C. Steinhäuser
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(2009). Role of astrocytes in epilepsy. In: Astrocytes in (patho)physiology of the nervous system. Parpura, V. and Haydon, P.G. (eds.). Springer, 649-671
Binder, D. and C. Steinhäuser
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(2010). Astrocyte dysfunction in epilepsy. Brain Res. Rev. 63:212-221
Seifert, G., G. Carmignoto and C. Steinhäuser
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(2010). Astrocyte dysfunction in temporal lobe epilepsy. Epilepsia 51(Suppl. 5):54
Steinhäuser, C. and G. Seifert
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(2010). Deletion of aquaporin-4 renders retinal glial cells more susceptible to osmotic stress. J. Neurosci. Res. 88:2877-2888
Pannicke, T., A. Wurm, I. Iandiev, M. Hollborn, R. Linnertz, D.K. Binder, L. Kohen, P. Wiedemann, C. Steinhäuser, A. Reichenbach, A. Bringmann
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(2010). Neuron-glia synapses inthe brain. BrainRes. Rev. 63:130-137
Bergles, D., R. Jabs and C. Steinhäuser
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(2010). Synaptic processes - The role of glial cells. Brain Res. Rev. 63:1
Deitmer, J. and C. Steinhäuser
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(2011). Gray Matter NG2 Cells Display Multiple Ca2+-Signaling Pathways and Highly Motile Processes. PLoS ONE 6:17575
Haberlandt, C., A. Derouiche, A. Wyczynski, J. Haseleu, J. Pohle, K. Karram, J. Trotter, G. Seifert, M. Frotscher, C. Steinhäuser, R. Jabs
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(2011). Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. Neuroscience 178:21-32
Hsu, M.S., M. Seldin, D.J. Lee, G. Seifert, C. Steinhäuser, D.K. Binder
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(2011). Role of astroglial Connexin30 in hippocampal gap junction coupling. Glia 59:511-519
Gosejacob, D., P. Dublin, P. Bedner, K. Hütlmann, J. Zhang, O. Tress, K. Willecke, F. Pfrieger, C. Steinhäuser, M. Theis
