Martin Theis
University of Bonn
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Martin Theis.
The Journal of Neuroscience | 2006
Anke Wallraff; Rüdiger Köhling; Uwe Heinemann; Martin Theis; Klaus Willecke; Christian Steinhäuser
Astrocytic gap junctions have been suggested to contribute to spatial buffering of potassium in the brain. Direct evidence has been difficult to gather because of the lack of astrocyte-specific gap junction blockers. We obtained mice with coupling-deficient astrocytes by crossing conditional connexin43-deficient mice with connexin30−/− mice. Similar to wild-type astrocytes, genetically uncoupled hippocampal astrocytes displayed negative resting membrane potentials, time- and voltage-independent whole-cell currents, and typical astrocyte morphologies. Astrocyte densities were also unchanged. Using potassium-selective microelectrodes, we assessed changes in potassium buffering in hippocampal slices of mice with coupling-deficient astrocytes. We demonstrate that astrocytic gap junctions accelerate potassium clearance, limit potassium accumulation during synchronized neuronal firing, and aid in radial potassium relocation in the stratum lacunosum moleculare. Furthermore, slices of mice with coupling-deficient astrocytes displayed a reduced threshold for the generation of epileptiform events. However, it was evident that radial relocation of potassium in the stratum radiatum was not dependent on gap junctional coupling. We suggest that the perpendicular array of individual astrocytes in the stratum radiatum makes these cells ideally suited for spatial buffering of potassium released by pyramidal cells, independent of gap junctions. In general, a surprisingly large capacity for K+ clearance was conserved in mice with coupling-deficient astrocytes, indicating that gap junction-dependent processes only partially account for K+ buffering in the hippocampus.
Circulation | 2004
Harold V.M. van Rijen; Dominik Eckardt; Joachim Degen; Martin Theis; Thomas Ott; Klaus Willecke; Habo J. Jongsma; Tobias Opthof; Jacques M.T. de Bakker
Background—Connexin 43 (Cx43) is a major determinant of conduction in the ventricular working myocardium of mammals. We investigated the effect of decreased Cx43 expression on conduction velocity and arrhythmogenesis using adult mice with inducible deletion of Cx43. Methods and Results—Cx43Cre-ER(T)/+ mice, in which 1 coding region of the Cx43 gene was replaced by Cre-ER(T), were mated to Cx43fl/fl mice, generating Cx43Cre-ER(T)/fl mice. Application of 4-hydroxytamoxifen (4-OHT) induced Cre-ER(T)–mediated deletion of the floxed Cx43 allele. Epicardial ventricular mapping using a 13×19 multiterminal electrode grid (300-&mgr;m spacing) was performed on Langendorff-perfused hearts from Cx43fl/fl plus carrier (n=10), Cx43fl/fl plus 4-OHT (n=10), Cx43 Cre-ER(T)/fl plus carrier (n=9), and Cx43Cre-ER(T)/fl plus 4-OHT (n=10). Cx43 protein amount in group 3 hearts was decreased by ≈50% compared with group 1. 4-OHT did not affect cardiac protein amounts in group 2 but decreased Cx43 expression up to 95% in group 4 compared with group 3. Epicardial activation of both left ventricle (LV) and right ventricle (RV) during sinus rhythm was similar in all groups. Conduction velocity (CV) changed only in group 4 animals. For RV (LV), longitudinal CV decreased from 38 (35) to 31.6 (33.6) and transverse CV from 24.4 (16.8) to 10.1 (11.3) cm/s. Dispersion of conduction in RV (LV) was increased by 91% (38%). Programmed stimulation resulted in ventricular arrhythmias in group 4 (7 of 10 mice) but never in groups 1 through 3. Conclusions—Heterozygous expression of Cx43 did not affect ventricular conduction velocity. Up to 95% decrease of Cx43 protein in 4-OHT–treated Cx43Cre-ER(T)/fl mice reduced conduction velocity and increased dispersion of conduction and propensity for ventricular arrhythmias.
American Journal of Pathology | 2004
Taizen Nakase; Goran Söhl; Martin Theis; Klaus Willecke; Christian C. Naus
Astrocytes secrete cytokines and neurotrophic factors to neurons, consistent with a neurosupportive role for astrocytes. However, in ischemic or metabolic insults, the function of astrocytic gap junctions composed mainly from connexin43 (Cx43) remains controversial. We have previously shown that heterozygous Cx43 null mice subjected to middle cerebral artery occlusion exhibited significantly enhanced stroke volume and apoptosis compared to wild-type mice. In this study, we used mice in which the human GFAP promoter-driven cre transgene deletes the floxed Cx43 gene in astrocytes, excluding the effects from reduced Cx43 expression in many other cell types as well as astrocytes. We induced focal brain ischemia in mice lacking Cx43 in astrocytes [Cre(+)] and control littermates [Cre(-)]. Cre(+) mice showed a significantly increased stroke volume and enhanced apoptosis, detected by terminal dUTP nick-end labeling and caspase-3 immunostaining, compared to Cre(-) mice. Inflammatory response assessed by the microglial marker CD11b was amplified in the penumbra of Cre(+) mice compared to that of Cre(-) mice. Our results suggest that astrocytic gap junctions could be important for the regulation of neuronal apoptosis and the inflammatory response after stroke. These findings support the view that astrocytes play a critical role in neuroprotection during ischemic insults.
Proceedings of the National Academy of Sciences of the United States of America | 2001
Eliseo A. Eugenin; Dominik Eckardt; Martin Theis; Klaus Willecke; Juan C. Sáez
Gap junctional communication between microglia was investigated at rat brain stab wounds and in primary cultures of rat and mouse cells. Under resting conditions, rat microglia (FITC-isolectin-B4-reactive cells) were sparsely distributed in the neocortex, and most (95%) were not immunoreactive for Cx43, a gap junction protein subunit. At brain stab wounds, microglia progressively accumulated over several days and formed aggregates that frequently showed Cx43 immunoreactivity at interfaces between cells. In primary culture, microglia showed low levels of Cx43 determined by Western blotting, diffuse intracellular Cx43 immunoreactivity, and a low incidence of dye coupling. Treatment with the immunostimulant bacterial lipopolysaccharide (LPS) or the cytokines interferon-γ (INF-γ) or tumor necrosis factor-α (TNF-α) one at a time did not increase the incidence of dye coupling. However, microglia treated with INF-γ plus LPS showed a dramatic increase in dye coupling that was prevented by coapplication of an anti-TNF-α antibody, suggesting the release and autocrine action of TNF-α. Treatment with INF-γ plus TNF-α also greatly increased the incidence of dye coupling and the Cx43 levels with translocation of Cx43 to cell–cell contacts. The cytokine-induced dye coupling was reversibly inhibited by 18α-glycyrrhetinic acid, a gap junction blocker. Cultured mouse microglia also expressed Cx43 and developed dye coupling upon treatment with cytokines, but microglia from homozygous Cx43-deficient mice did not develop significant dye coupling after treatment with either INF-γ plus LPS or INF-γ plus TNF-α. This report demonstrates that microglia can communicate with each other through gap junctions that are induced by inflammatory cytokines, a process that may be important in the elaboration of the inflammatory response.
Genesis | 2001
Martin Theis; Cor de Wit; Thorsten M. Schlaeger; Dominik Eckardt; Olaf Krger; Britta Dring; Werner Risau; Urban Deutsch; Ulrich Pohl; Klaus Willecke
Summary: The murine gap junction protein connexin43 (Cx43) is expressed in blood vessels, with vastly different contribution by endothelial and smooth muscle cells. We have used the Cre recombinase under control of TIE2 transcriptional elements to inactivate a floxed Cx43 gene specifically in endothelial cells. Cre‐mediated deletion led to replacement of the Cx43 coding region by a lacZ reporter gene. This allowed us to monitor the extent of deletion and to visualize the endothelial expression pattern of Cx43. We found widespread endothelial expression of the Cx43 gene during embryonic development, which became restricted largely to capillaries and small vessels in all adult organs examined. Mice lacking Cx43 in endothelium did not exhibit altered blood pressure, in contrast to mice deficient in Cx40. Our results show that lacZ activation after deletion of the target gene allows us to determine the extent of cell type‐specific deletion after phenotypical investigation of the same animal. genesis 29:1–13, 2001.
Proceedings of the National Academy of Sciences of the United States of America | 2003
Martin Theis; Kausik Si; Eric R. Kandel
Cytoplasmic polyadenylation element-binding (CPEB) proteins control polyadenylation-induced translation in early development. Studies in oocytes led to the delineation of Xenopus CPEB, the first member of the family to be identified, and its mouse homologue mCPEB-1. Recently, a second mouse family member, mCPEB-2, has been described in germ cells. Increasing evidence also implicates CPEB proteins as being important in the hippocampus, where these proteins are thought to regulate local protein synthesis and synaptic plasticity. We therefore carried out a systematic screen for CPEB genes in the mouse brain and report two previously undescribed gene family members: mCPEB-3 and -4. We next examined the expression of all four genes in the hippocampus and found that mCPEB-1, -2, and -4 transcripts are expressed in the principal cell layer in the CA3 and CA1 region and in the dentate gyrus of the hippocampus. mCPEB-3 was barely expressed in naïve animals but together with mCPEB-4 was strongly up-regulated after injection of kainate to initiate seizure activity. Whereas mCPEB-1 is regulated by the Aurora kinase, mCPEB-2, -3, and -4 do not contain Aurora kinase phosphorylation sites. However, alternative splice isoforms of mCPEB-2, -3, and -4 encode the so-called B region with phosphorylation sites for cAMP-dependent protein kinase, calcium/calmodulin-dependent protein kinase II, and S6 kinase. Only isoforms that encode the B region were expressed in the principal cell layer. Coexpression of mCPEB-1 and the B region-containing splice isoforms suggests that a variety of different signaling pathways can recruit CPEB activity in hippocampal neurons.
Journal of Cell Science | 2006
Dong Jin Chung; Charlles Heldan de Moura Castro; Marcus Watkins; Joseph P. Stains; Min Young Chung; Vera Lúcia Szejnfeld; Klaus Willecke; Martin Theis; Roberto Civitelli
Connexin43 (Cx43) is involved in bone development, but its role in adult bone homeostasis remains unknown. To overcome the postnatal lethality of Cx43 null mutation, we generated mice with selective osteoblast ablation of Cx43, obtained using a Cx43fl allele and a 2.3-kb fragment of the α1(I) collagen promoter to drive Cre in osteoblasts (ColCre). Conditionally osteoblast-deleted ColCre;Cx43–/fl mice show no malformations at birth, but develop low peak bone mass and remain osteopenic with age, exhibiting reduced bone formation and defective osteoblast function. By both radiodensitometry and histology, bone mineral content increased rapidly and progressively in adult Cx43+/fl mice after subcutaneous injection of parathyroid hormone (PTH), an effect significantly attenuated in ColCre;Cx43–/fl mice, with Cx43–/fl exhibiting an intermediate response. Attenuation of PTH anabolic action was associated with failure to increase mineral apposition rate in response to PTH in ColCre;Cx43–/fl, despite an increased osteoblast number, suggesting a functional defect in Cx43-deficient bone-forming cells. In conclusion, lack of Cx43 in osteoblasts leads to suboptimal acquisition of peak bone mass, and hinders the bone anabolic effect of PTH. Cx43 represents a potential target for modulation of bone anabolism.
The Journal of Neuroscience | 2009
Cima Cina; Karen Maass; Martin Theis; Klaus Willecke; John F. Bechberger; Christian C. Naus
During brain development, young neurons closely associate with radial glial while migrating from the ventricular zone (VZ) to the cortical plate (CP) of the neocortex. It has been shown previously that gap junctions are needed for this migration to occur properly, but the precise mechanism responsible is still in question. Here, we used Cre recombinase, driven by the nestin promoter, to conditionally knock-out a floxed coding DNA of the connexin43 (Cx43) gene in mice. Radial glia in the VZ normally express connexin43. They undergo divisions that produce neurons and astrocytes and serve as migratory guides for the daughter cells that they produce. Based on histological analysis, we suggest that removing Cx43 from radial glia alters the normal lamination of the mouse neocortex. To monitor newborn neurons during development, we introduced a plasmid containing green fluorescent protein driven by a neuronal (Tα1 tubulin) promoter into the embryonic neocortex using in utero electroporation. The transfected migrating neurons remain in the VZ/intermediate zone (IZ) of the Cx43 conditional knock-out (Cx43cKO) animals, whereas in Cx43fl/fl mice, neurons migrate through the IZ into the CP, indicating that deletion of Cx43 from nestin-positive cells disrupts neuronal migration. We were able to rescue migration of Cx43cKO neurons by electroporating a cytomegalovirus–Cx43 expression plasmid into the embryonic cortex. In contrast, a C-terminal truncated form of Cx43 failed to rescue neuronal migration. In addition, Cx43K258stop mice, in which Cx43 lacks the last 125 amino acid residues of the cytoplasmic C-terminal domain, gave results similar to those seen with the Cx43cKO mice. This study illustrates that deletion of the C-terminal domain of Cx43 alters neuronal migration in the neocortex.
Brain Research Reviews | 2010
Christian Giaume; Martin Theis
This review gives an overview of connexin expression in glial cells of the central nervous system, the different modes of connexin action, including gap junctional channels and hemichannels, as well as the available methodologies to measure their activity. We summarize the strengths and limitations of current pharmacological and genetic approaches to interfere with connexin channel functions. We outline new avenues not only to study specific mechanisms by which connexins exert these functions but also to selectively investigate well-defined coupling compartments among glial networks.
Proceedings of the National Academy of Sciences of the United States of America | 2009
Albrecht Kunze; Marga Rubenecia Congreso; Christian Hartmann; Anke Wallraff-Beck; Kerstin Hüttmann; Peter Bedner; Robert Pascal Requardt; Gerald Seifert; Christoph Redecker; Klaus Willecke; Alexander Pfeifer; Martin Theis; Christian Steinhäuser
In the adult dentate gyrus, radial glia-like cells represent putative stem cells generating neurons and glial cells. Here, we combined patch-clamp recordings, biocytin filling, immunohistochemistry, single-cell transcript analysis, and mouse transgenics to test for connexin expression and gap junctional coupling of radial glia-like cells and its impact on neurogenesis. Radial glia-like cells were identified in mice expressing EGFP under control of the nestin and gfap promoters. We show that a majority of Radial glia-like cells are coupled and express Cx43. Neuronal precursors were not coupled. Mice lacking Cx30 and Cx43 in GFAP-positive cells displayed almost complete inhibition of proliferation and a significant decline in numbers of radial glia-like cells and granule neurons. Inducible virus-mediated ablation of connexins in the adult hippocampus also reduced neurogenesis. These findings strongly suggest the requirement of connexin expression by radial glia-like cells for intact neurogenesis in the adult brain and point to possible communication pathways of these cells.