NeuroGLIA Consortium: neuron-astroglia in brain function and dysfunction

Consortium Coordinator

Other consortium members

Brief description and aims of work

Research work at the Institute of Cellular Neurosciences is focussed on the investigation of glial cells and their role in information processing in the normal and diseased brain. To unravel mechanisms underlying neuron-to-glia interaction as well as glial cell heterogeneity, we apply a combination of electrophysiological, molecular and imaging techniques. Of particular interest is the hippocampus, a brain region that is important for learning and memory. We investigate cellular properties in acute preparations, either after fresh cell isolation or in acute brain slices of mice and rats. These projects are supported by the DFG Priority Program SPP1172 Glia-Synapse.

A second focus of our research is on the analysis of human epilepsy. Here we apply our methods to glial cells and neurons in acute, live hippocampal specimens obtained from neurosurgical treatment of patients suffering from pharmacoresistant temporal lobe epilepsy. In addition, animal models of epilepsy are used. The goal is to better understand the role of glial cells in the generation and spread of seizure activity. This topic is also funded by DFG and embedded into the Collaborative Research Centre SFB/TR3 Mesial Temporal Lobe Epilepsies.

In 2006, a DFG Junior Research Group associated with the SFB/TR3 was established at the Institute of Cellular Neurosciences. This group, headed by Dr. Martin Theis, is working on the role of cytoplasmic polyadenylation element binding (CPEB) proteins, a family of translational regulators, in development and progression of epilepsy. CPEBs are RNA binding proteins expressed in neurons and in glial cells which control the translation of selected target mRNAs. These mRNAs encode proteins relevant for neuronal activity and its pathological manifestations, as well as proteins which define the cellular identity of astroglial cells. Our group is also interested in the role of CPEBs in microglia. We use genetic and pharmacological approaches in a mouse model of temporal lobe epilepsy and complement these studies with the investigation of changes in human CPEB expression and function in specimens obtained from epilepsy patients.

Previous findings

In 1992 we published the first patch clamp recordings of identified glial cells in acute slices of mouse hippocampus (Ref. 31).

In 1994, we detected that two functionally different astroglial subpopulations exist in the hippocampus and termed them 'complex' and 'passive' glial cells (Ref. 28).

Between 2000 and 2004, our group performed the first comparative molecular and functional analyses of astroglial cells in hippocampal specimens from patients with sclerotic vs nonsclerotic forms of temporal lobe epilepsy (Refs. 7,12,18,19).

In 2003 and 2004, combined molecular, functional and immunohistochemical analyses revealed the coexistence of at least two distinct types of cells with astroglial properties in the hippocampus, GluR cells and GluT cells (Refs. 6,8).

In 2005 we could demonstrated that glial cells of the GluR subtype receive direct synaptic input from glutamatergic and GABAergic neurons (Ref. 3).

In 2006, we revealed the role of gap junctional communication of astrocytes in potassium buffering in different subregions of the hippocampus (Ref. 2).

Implications of our research

Recent work has established that astroglial cells play a much more active role in information processing than hitherto anticipated. Our work aims at unravelling mechanisms of neuron-glia interactions and its physiological and pathophysiological consequences. Particularly, we try to elucidate the role distinct types glial cell have in the pathogenesis of epilepsy, which hopefully will lead to the identification of new targets allowing for the development of more effective therapies and improved treatment of this disease.

Selected references on astroglia

Original articles

1. Lu YB, Franze K, Seifert G, Steinhäuser C, Kirchhoff F, Wolburg H, Guck J, Janmey P, Wei EQ, Käs J, Reichenbach A (2006) Viscoelastic properties of individual glial cells and neurons in the CNS. Proc. Natl. Acad. Sci. U.S.A. 103:17759-64.
2. Wallraff A, Köhling R, Heinemann U, Theis M, Willecke K, Steinhäuser C (2006) The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J. Neurosci. 26:5438-47.
3. Jabs R, Pivneva T, Hüttmann K, Wyczynski A, Nolte C, Kettenmann H, Steinhäuser C (2005) Synaptic transmission onto hippocampal glial cells with hGFAP promoter activity. J. Cell. Sci. 118:3791-803.
4. Vaithianathan T, Matthias K, Bahr B, Schachner M, Suppiramaniam V, Dityatev A, Steinhaüser C (2004) Neural cell adhesion molecule-associated polysialic acid potentiates alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor currents. J. Biol. Chem. 279:47975-84.
5. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhäuser C, Pilati E, Volterra A (2004) Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat. Neurosci. 7:613-20.
6. Wallraff A, Odermatt B, Willecke K, Steinhäuser C (2004) Distinct types of astroglial cells in the hippocampus differ in gap junction coupling. Glia 48:36-43.
7. Seifert G, Hüttmann K, Schramm J, Steinhäuser C (2004) Enhanced relative expression of GluR1 flip AMPA receptor subunits in hippocampal astrocytes of epilepsy patients with Ammon's horn sclerosis. J. Neurosci. 24:1996-2003.
8. Matthias K, Kirchhoff F, Seifert G, Hüttmann K, Matyash M, Kettenmann H, Steinhäuser C (2003) Segregated expression of AMPA-type glutamate receptors and glutamate transporters defines distinct astrocyte populations in the mouse hippocampus. J. Neurosci. 23:1750-8.
9. Scheffler B, Schmandt T, Schröder W, Steinfarz B, Husseini L, Wellmer J, Seifert G, Karram K, Beck H, Blümcke I, Wiestler OD, Steinhäuser C, Brüstle O (2003) Functional network integration of embryonic stem cell-derived astrocytes in hippocampal slice cultures. Development 130:5533-41.
10. Hüttmann K, Sadgrove M, Wallraff A, Hinterkeuser S, Kirchhoff F, Steinhäuser C, Gray WP (2003) Seizures preferentially stimulate proliferation of radial glia-like astrocytes in the adult dentate gyrus: functional and immunocytochemical analysis. Eur. J. Neurosci. 18:2769-78.
11. Makara JK, Rappert A, Matthias K, Steinhäuser C, Spät A, Kettenmann H (2003) Astrocytes from mouse brain slices express ClC-2-mediated Cl^- currents regulated during development and after injury. Mol. Cell. Neurosci. 23:521-30.
12. Seifert G, Weber M, Schramm J, Steinhäuser C (2003) Changes in splice variant expression and subunit assembly of AMPA receptors during maturation of hippocampal astrocytes. Mol. Cell. Neurosci. 22:248-58.
13. Odermatt B, Wellershaus K, Wallraff A, Seifert G, Degen J, Euwens C, Fuss B, Büssow H, Schilling K, Steinhäuser C, Willecke K (2003) Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J. Neurosci. 23:4549-59.
14. Theis M, Jauch R, Zhuo L, Speidel D, Wallraff A, Döring B, Frisch C, Söhl G, Teubner B, Euwens C, Huston J, Steinhäuser C, Messing A, Heinemann U, Willecke K (2003) Accelerated hippocampal spreading depression and enhanced locomotory activity in mice with astrocyte-directed inactivation of connexin43. J. Neurosci. 23:766-76.
15. Schröder W, Seifert G, Hüttmann K, Hinterkeuser S, Steinhäuser C (2002) AMPA receptor-mediated modulation of inward rectifier K⁺ channels in astrocytes of mouse hippocampus. Mol. Cell. Neurosci. 19:447-58.
16. Seifert G, Schröder W, Hinterkeuser S, Schumacher T, Schramm J, Steinhäuser C (2002) Changes in flip/flop splicing of astroglial AMPA receptors in human temporal lobe epilepsy. Epilepsia 43 Suppl 5:162-7.
17. Kukley M, Barden JA, Steinhäuser C, Jabs R (2001) Distribution of P2X receptors on astrocytes in juvenile rat hippocampus. Glia 36:11-21.
18. Hinterkeuser S, Schröder W, Hager G, Seifert G, Blümcke I, Elger CE, Schramm J, Steinhäuser C (2000) Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances. Eur. J. Neurosci. 12:2087-96.
19. Schröder W, Hinterkeuser S, Seifert G, Schramm J, Jabs R, Wilkin GP, Steinhäuser C (2000) Functional and molecular properties of human astrocytes in acute hippocampal slices obtained from patients with temporal lobe epilepsy. Epilepsia 41 Suppl 6:S181-4.
20. Kunzelmann P, Schröder W, Traub O, Steinhäuser C, Dermietzel R, Willecke K (1999) Late onset and increasing expression of the gap junction protein connexin30 in adult murine brain and long-term cultured astrocytes. Glia 25:111-9.
21. Schröder W, Hager G, Kouprijanova E, Weber M, Schmitt AB, Seifert G, Steinhäuser C (1999) Lesion-induced changes of electrophysiological properties in astrocytes of the rat dentate gyrus. Glia 28:166-74.
22. Seifert G, Rehn L, Weber M, Steinhäuser C (1997) AMPA receptor subunits expressed by single astrocytes in the juvenile mouse hippocampus. Brain Res. Mol. Brain Res. 47:286-94.
23. Akopian G, Kuprijanova E, Kressin K, Steinhäuser C (1997) Analysis of ion channel expression by astrocytes in red nucleus brain stem slices of the rat. Glia 19:234-46.
24. Seifert G, Zhou M, Steinhäuser C (1997) Analysis of AMPA receptor properties during postnatal development of mouse hippocampal astrocytes. J. Neurophysiol. 78:2916-23.
25. Akopian G, Kressin K, Derouiche A, Steinhäuser C (1996) Identified glial cells in the early postnatal mouse hippocampus display different types of Ca²⁺ currents. Glia 17:181-94.
26. Seifert G, Steinhäuser C (1995) Glial cells in the mouse hippocampus express AMPA receptors with an intermediate Ca²⁺ permeability. Eur. J. Neurosci. 7:1872-81.
27. Kressin K, Kuprijanova E, Jabs R, Seifert G, Steinhäuser C (1995) Developmental regulation of Na⁺ and K⁺ conductances in glial cells of mouse hippocampal brain slices. Glia 15:173-87.
28. Steinhäuser C, Jabs R, Kettenmann H (1994) Properties of GABA and glutamate responses in identified glial cells of the mouse hippocampal slice. Hippocampus 4:19-35.
29. Jabs R, Kirchhoff F, Kettenmann H, Steinhäuser C (1994) Kainate activates Ca²⁺-permeable glutamate receptors and blocks voltage-gated K⁺ currents in glial cells of mouse hippocampal slices. Pflugers Arch. 426:310-9.
30. Steinhäuser C, Kressin K, Kuprijanova E, Weber M, Seifert G (1994) Properties of voltage-activated Na⁺ and K⁺ currents in mouse hippocampal glial cells in situ and after acute isolation from tissue slices. Pflugers Arch. 428:610-20.
31. Steinhäuser C, Berger T, Frotscher M, Kettenmann H (1992) Heterogeneity in the membrane current pattern of identified glial cells in the hippocampal slice. Eur. J. Neurosci. 4:472-484.

Reviews

1. Binder DK, Steinhäuser C (2006) Functional changes in astroglial cells in epilepsy. Glia 54:358-68.
2. Seifert G, Schilling K, Steinhäuser C (2006) Astrocyte dysfunction in neurological disorders: a molecular perspective. Nat. Rev. Neurosci. 7:194-206.
3. Volterra A, Steinhäuser C (2004) Glial modulation of synaptic transmission in the hippocampus. Glia 47:249-57.
4. Krebs C, Hüttmann K, Steinhäuser C (2004) The Forgotten Brain Emerges Sci. Am. Mind 14:40-43.
5. Steinhäuser C, Seifert G (2002) Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur. J. Pharmacol. 447:227-37.
6. Seifert G, Steinhäuser C (2001) Ionotropic glutamate receptors in astrocytes. Prog. Brain Res. 132:287-99.
7. Verkhratsky A, Steinhäuser C (2000) Ion channels in glial cells. Brain Res. Brain Res. Rev. 32:380-412.
8. Condorelli DF, Conti F, Gallo V, Kirchhoff F, Seifert G, Steinhäuser C, Verkhratsky A, Yuan X (1999) Expression and functional analysis of glutamate receptors in glial cells. Adv. Exp. Med. Biol. 468:49-67.
9. Steinhäuser C, Gallo V (1996) News on glutamate receptors in glial cells. Trends Neurosci. 19:339-45.
10. Steinhäuser C (1993) Electrophysiologic characteristics of glial cells. Hippocampus 3 Spec No:113-23.

Selected collaborations,
past and present

• Devin Binder · Neurological Surgery, University of Irvine, California, USA
• Klaus Willecke · Insitute of Genetics, University of Bonn, Germany
• Uwe Heinemann · Institute of Neurophysiology, Charité, Berlin, Germany
• Frank Kirchhoff · MPI of Experimental Medicine, Göttingen, Germany
• Jacky Trotter · Molecular Cell Biology, University of Mainz, Germany
• Andrea Volterra · Cell Biology and Morphology, University of Lausanne, Switzerland
• Helmut Kettenmann · Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Berlin, Germany