JUNCTIONAL COMMUNICATION AND NEURO-GLIO-VASCULAR INTERACTIONS
Director: Christian GIAUME, DR1 Cnrs
The main focus of our research is the definition of the properties and the understanding of the multiple roles of connexins expressed in glial cells, particularly in astrocytes. Connexins are membrane proteins that form gap junction channels allowing direct exchanges of ions and signaling molecules (energy metabolites, cyclic nucleotides, second messengers, gliotransmitters....) between the cytoplasm of adjacent cells. These gap junctions constitute the basis of astroglial networks providing a ionic/biochemical/metabolic coordination of these communicating cells.,Moreover, in defined conditions connexins can also operate as hemichannels allowing for exchanges between cytoplasmic and extracellular compartments. This hemichannel function is also contributed by pannexins, another membrane protein family expressed in neurons and in glial cells. It is now recognized that astrocytes interact dynamically with neurons modifying their activity and survival and are also active players at the gliovascular interface. However, these interactions are generally considered at an individual level. Our strategy is to study neuroglial and gliovascular interactions at a more integrated level, resulting of an interplay of neuronal circuits/vascular system with astroglial networks supported by gap junctions and/or hemichannels.
Gap junction (GJ) and hemichannel (HC) molecular organization. Diagram showing how connexin GJ channels form a GJ plaque at a point of close contact between two cells. Each GJ channel is formed by two connexin HCs docked together. The right-hand diagrams show the topology of a pannexin channel (top, these channels do not form GJ channels), a GJ plaque (center) and a connexin HC (bottom) at the plasma membrane. Connexin and pannexin have both four transmembrane domains with amino and carboxy termini on the cytoplasmic side, two extracellular loops, and one cytoplasmic loop.
Our main research topics are:
1) The definition of the properties and role of astroglial networks in brain regions characterized by a strong anatomo-functional organization of neuronal circuits (somatosensory cortex, olfactory bulb);
2) The identification of the role of astroglial connexins/pannexins in the regulation of sleep-wake cycle;
3) The understanding of their contribution to brain metabolism by considering the uptake and the trafficking of energy metabolites and their delivery to active neurons;
4) The determination of the role of astroglial connexins in the blood brain barrier physiology as well as their contribution to the control of blood flow;
5) The development of new molecular approaches with astrocyte-directed tools (conditional and cell type targeted transgenic mice, lentiviral constructs) to study channels and non-channels functions of connexins/pannexins in neuroglial and gliovascular interactions.
6) Our research covers also pathological situations, such as Alzheimer's disease and neuroinflammation, using pharmacological and genetic animal models in which reactive gliosis is associated with changes in the expression of connexins/pannexins in astrocytes.
These projects are developed:
1) Using a multidisciplinary approach combining electrophysiology, calcium imaging, dye injections, cellular and molecular biology, biochemistry, immunohistochemistry, confocal and bi-photon microscopy, applied on in vitro (cultures, acute brain slices) and in vivo models with the aim to associating protein expression and function.
2) Through national and international (Germany, Spain, Switzerland, Chile, Canada) collaborations that provide specific animal models and pharmacological tools as well as high-tech approaches.
In summary, our research aims at defining cellular and molecular mechanisms involved in neuroglial and gliovascular interactions as well as identifying glial targets that could represent the basis for alternative strategies to act on neuronal dysfunction or death.
Astroglial networks in the olfactory glomeruli revealed by dialysis of sulforhodamin B (red) through a patch clamp pipette. Cell bodies stained by the Nissl reagent (blue) define the glomerular structures. Scales : 50μm, inset 30ms/1nA.
Astroglial perivascular connexin43 in the adult mouse cortex. Confocal microscopy projection of a 20 µm-large blood vessel. Endothelial cells are immunolabeled with Pecam (gray), and astrocyte endfeet enwrapping the vessel are immunolabeled with GFAP (green) and connexin43 (red).
Connexin 43 immunoreactivity (green) is enhanced in the reactive astrocytes (GFAP-stained in red) at ß-amyloid plaques (blue) in a human temporal cortex section from a patient affected by the Alzheimer's disease. Calibration: 20 μm.
SELECTED PUBLICATIONS 2008-2013
- Boulay A.-C., Burbassi S., Lorenzo H.-K., Loew D., Ezan P., Giaume C. & Cohen-Salmon M. (2013a), Bmcc1s interacts with the phosphate-activated glutaminase in the brain. Biochimie 95, 799-807.
- Boulay A.-C., del Castillo F.J., Giraudet F., Hamard G., Giaume C., Petit C., Avan P. & Cohen-Salmon M. (2013b), Hearing is normal without connexin30. J. Neurosci. 33, 430-434.
- Liu X., Petit J.-M., Ezan P., Gyger J., Magistretti P. & Giaume C. (2013), The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes. Neuropharmacology, May 9.
- Arama J., Boulay A.-C., Bosc C., Delphin C., Loew D., Rostaing P., Amigou E., Ezan P., Wingertsmann L., Guillaud L., Andrieux A., Giaume C. & Cohen-Salmon M. (2012), Bmcc1s, a novel brain-isoform of Bmcc1, affects cell morphology by regulating MAP6/STOP functions. PLoS ONE 7, e35488.
- Gangoso E., Ezan P., Valle-Casuso J.C., Herrero-González S., Koulakoff A., Medina J.M., Giaume C. & Tabernero A. (2012), Reduced connexin43 expression correlates with c-Src activation, proliferation, and glucose uptake in reactive astrocytes after an excitotoxic insult. Glia 60, 2040-2049.
- Giaume, C., Liu, X., (2012), From a glial syncytium to a more restricted and specific glial networking. J. Physiol. Paris 106, 34-39.
- Giaume C., Orellana J.A., Abudara V. & Sáez J.C. (2012), Connexin-based channels in astrocytes: how to study their properties. Methods Mol. Biol. 814, 283-303.
- Koulakoff A., Mei X., Orellana J.A., Sáez J.C. & Giaume C. (2012), Glial connexin expression and function in the context of Alzheimer's disease. Biochimica Biophysica Acta, 1818:2048-57.
- Orellana J.A., von Bernhardi R., Giaume C. & Sáez J.C. (2012), Glial hemichannels and their involvement in aging and neurodegenerative diseases. Rev Neurosci 23, 163-177.
- Tencé M., Ezan P., Amigou E. & Giaume C. (2012), Increased interaction of connexin43 with zonula occludens-1 during inhibition of gap junctions by G protein-coupled receptor agonists. Cell. Signal. 24, 86-98.
- Theis M. & Giaume C., (2012), Connexin-based intercellular communication and astrocyte heterogeneity. Brain Res. 1487, 88-98.
- Ezan P., André P., Cisternino S., Saubaméa B., Boulay A.C., Doutremer S., Thomas M.A., Quenech'du N., Giaume C. & Cohen-Salmon M. (2012), Deletion of astroglial connexins weakens the blood-brain barrier. Journal of Cerebral Blood Flow and Metabolism, 32:1457-67.
- Roux L., Benchenane K., Rothstein J.D., Bonvento G. & Giaume C. (2011), Plasticity of astroglial networks in olfactory glomeruli. Proceedings of the National Academy of Sciences (USA), 108:18442-6.
- Orellana J.A., Shoji K.F., Abudara V., Ezan P., Amigou E., Sáez P.J., Jiang J.X., Naus C.C., Sáez J.C. & Giaume C. (2011), Amyloid β-induced death in neurons involves glial and neuronal hemichannels. Journal of Neuroscience, 31:4962-77.
- Giaume C., Koulakoff A., Roux L., Holcman D. & Rouach N. (2010), Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci, 11:87-99.
- Rouach N., Koulakoff A., Abudara V., Willecke K. & Giaume C. (2008), Astroglial metabolic networks sustain hippocampal synaptic transmission. Science, 322:1551-5.
- Koulakoff A., Ezan P. & Giaume C. (2008), Neurons control the expression of connexin 30 and connexin 43 in mouse cortical astrocytes. Glia, 56:1299-311.
- Houades V., Koulakoff A., Ezan P., Seif I. & Giaume C. (2008), Gap junction-mediated astrocytic networks in the mouse barrel cortex. Journal of Neuroscience, 28:5207-17.
Giaume Christian, DR1 CNRS
Koulakoff Annette, MdC CDF
Postdoctoral fellows and Students:
Liu Xinhe, PhD student ENP
Yi Chenju, Postdoc FRM
Jeanson Tiffany, PhD student CIFRE
Amigou Edwige, ITA CDF
Ezan Pascal, ITA CDF