Laboratory of Excellence and Paris Science Lettre Research University

Paris, France

Laboratory of Excellence and Paris Science Lettre Research University

Paris, France
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Boulay A.-C.,The Interdisciplinary Center | Boulay A.-C.,University Pierre and Marie Curie | Boulay A.-C.,Laboratory of Excellence and Paris Science Lettre Research University | Saubamea B.,University Paris Diderot | And 8 more authors.
Frontiers in Cellular Neuroscience | Year: 2015

Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction proteins Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30A/A; A means deleted allele) we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding ɣ-Sarcoglycan (ɣ-SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30T5M/T5M mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC) molecules in the cerebrovascular system and showed the presence of α-, β-, δ-, ɣ-, ɛ- and ʕ- SG, as well as Sarcospan. Their expression was however not modified in Cx30Δ/Δ. These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, ɣ-SG, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions. © 2015 Boulay, Saubaméa, Cisternino, Mignon, Mazeraud, Jourdren, Blugeon and Cohen-Salmon.


Liu X.,The Interdisciplinary Center | Liu X.,University Pierre and Marie Curie | Liu X.,Laboratory of Excellence and Paris Science Lettre Research University | Gangoso E.,The Interdisciplinary Center | And 14 more authors.
GLIA | Year: 2016

Astrocytes represent a major non-neuronal cell population actively involved in brain functions and pathologies. They express a large amount of gap junction proteins that allow communication between adjacent glial cells and the formation of glial networks. In addition, these membrane proteins can also operate as hemichannels, through which "gliotransmitters" are released, and thus contribute to neuroglial interaction. There are now reports demonstrating that alterations of astroglial gap junction communication and/or hemichannel activity impact neuronal and synaptic activity. Two decades ago we reported that several general anesthetics inhibited gap junctions in primary cultures of astrocytes (Mantz et al., (1993) Anesthesiology 78(5):892-901). As there are increasing studies investigating neuroglial interactions in anesthetized mice, we here updated this previous study by employing acute cortical slices and by characterizing the effects of general anesthetics on both astroglial gap junctions and hemichannels. As hemichannel activity is not detected in cortical astrocytes under basal conditions, we treated acute slices with the endotoxin LPS or proinflammatory cytokines to induce hemichannel activity in astrocytes, which in turn activated neuronal hemichannels. We studied two extensively used anesthetics, propofol and ketamine, and the more recently developed dexmedetomidine. We report that these drugs have differential inhibitory effects on gap junctional communication and hemichannel activity in astrocytes when used in their respective, clinically relevant concentrations, and that dexmedetomidine appears to be the least effective on both channel functions. In addition, the three anesthetics have similar effects on neuronal hemichannels. Altogether, our observations may contribute to optimizing the selection of anesthetics for in vivo animal studies. © 2016 Wiley Periodicals, Inc.


di Lullo E.,The Interdisciplinary Center | di Lullo E.,Collège de France | di Lullo E.,University Pierre and Marie Curie | di Lullo E.,Laboratory of Excellence and Paris Science Lettre Research University | And 18 more authors.
Development | Year: 2011

Homeoprotein transcription factors play fundamental roles in development, ranging from embryonic polarity to cell differentiation and migration. Research in recent years has underscored the physiological importance of homeoprotein intercellular transfer in eye field development, axon guidance and retino-tectal patterning, and visual cortex plasticity. Here, we have used the embryonic chick neural tube to investigate a possible role for homeoprotein Pax6 transfer in oligodendrocyte precursor cell (OPC) migration. We report the extracellular expression of Pax6 and the effects of gain and loss of extracellular Pax6 activity on OPCs. Open book cultures with recombinant Pax6 protein or Pax6 blocking antibodies, as well as in ovo gene transfer experiments involving expression of secreted Pax6 protein or secreted Pax6 antibodies, provide converging evidences that OPC migration is promoted by extracellular Pax6. The paracrine effect of Pax6 on OPC migration is thus a new example of direct non-cell autonomous homeoprotein activity. © 2011.


Giaume C.,The Interdisciplinary Center | Giaume C.,University Pierre and Marie Curie | Giaume C.,Laboratory of Excellence and Paris Science Lettre Research University | Leybaert L.,Ghent University | And 3 more authors.
Frontiers in Pharmacology | Year: 2013

Functional interaction between neurons and glia is an exciting field that has expanded tremendously during the past decade. Such partnership has multiple impacts on neuronal activity and survival. Indeed, numerous findings indicate that glial cells interact tightly with neurons in physiological as well as pathological situations. One typical feature of glial cells is their high expression level of gap junction protein subunits, named connexins (Cxs), thus the membrane channels they form may contribute to neuroglial interaction that impacts neuronal activity and survival. While the participation of gap junction channels in neuroglial interactions has been regularly reviewed in the past, the other channel function of Cxs, i.e., hemichannels located at the cell surface, has only recently received attention. Gap junction channels provide the basis for a unique direct cell-to-cell communication, whereas Cx hemichannels allow the exchange of ions and signaling molecules between the cytoplasm and the extracellular medium, thus supporting autocrine and paracrine communication through a process referred to as "gliotransmission," as well as uptake and release of metabolites. More recently, another family of proteins, termed pannexins (Panxs), has been identified. These proteins share similar membrane topology but no sequence homology with Cxs. They form multimeric membrane channels with pharmacology somewhat overlapping with that of Cx hemichannels. Such duality has led to several controversies in the literature concerning the identification of the molecular channel constituents (Cxs versus Panxs) in glia. In the present review, we update and discuss the knowledge of Cx hemichannels and Panx channels in glia, their properties and pharmacology, as well as the understanding of their contribution to neuroglial interactions in brain health and disease. © 2013 Giaume, Giaume, Naus and Sáez.


Arama J.,The Interdisciplinary Center | Arama J.,University Pierre and Marie Curie | Arama J.,Laboratory of Excellence and Paris Science Lettre Research University | Boulay A.-C.,The Interdisciplinary Center | And 21 more authors.
PLoS ONE | Year: 2012

The BCH (BNIP2 and Cdc42GAP Homology) domain-containing protein Bmcc1/Prune2 is highly enriched in the brain and is involved in the regulation of cytoskeleton dynamics and cell survival. However, the molecular mechanisms accounting for these functions are poorly defined. Here, we have identified Bmcc1s, a novel isoform of Bmcc1 predominantly expressed in the mouse brain. In primary cultures of astrocytes and neurons, Bmcc1s localized on intermediate filaments and microtubules and interacted directly with MAP6/STOP, a microtubule-binding protein responsible for microtubule cold stability. Bmcc1s overexpression inhibited MAP6-induced microtubule cold stability by displacing MAP6 away from microtubules. It also resulted in the formation of membrane protrusions for which MAP6 was a necessary cofactor of Bmcc1s. This study identifies Bmcc1s as a new MAP6 interacting protein able to modulate MAP6-induced microtubule cold stability. Moreover, it illustrates a novel mechanism by which Bmcc1 regulates cell morphology. © 2012 Arama et al.


Abudara V.,The Interdisciplinary Center | Abudara V.,University Pierre and Marie Curie | Abudara V.,Laboratory of Excellence and Paris Science Lettre Research University | Abudara V.,University of the Republic of Uruguay | And 19 more authors.
GLIA | Year: 2015

Glia plays an active role in neuronal functions and dysfunctions, some of which depend on the expression of astrocyte connexins, the gap junction channel and hemichannel proteins. Under neuroinflammation triggered by the endotoxin lipopolysacharide (LPS), microglia is primary stimulated and releases proinflammatory agents affecting astrocytes and neurons. Here, we investigate the effects of such microglial activation on astrocyte connexin-based channel functions and their consequences on synaptic activity in an ex vivo model. We found that LPS induces astroglial hemichannel opening in acute hippocampal slices while no change is observed in gap junctional communication. Based on pharmacological and genetic approaches we found that the LPS-induced hemichannel opening is mainly due to Cx43 hemichannel activity. This process primarily requires a microglial stimulation resulting in the release of at least two proinflammatory cytokines, IL-1β and TNF-α. Consequences of the hemichannel-mediated increase in membrane permeability are a calcium rise in astrocytes and an enhanced glutamate release associated to a reduction in excitatory synaptic activity of pyramidal neurons in response to Schaffer's collateral stimulation. As a whole our findings point out astroglial hemichannels as key determinants of the impairment of synaptic transmission during neuroinflammation. © 2015 Wiley Periodicals, Inc.


Genoud C.,University of Lausanne | Genoud C.,Friedrich Miescher Institute for Biomedical Research | Houades V.,The Interdisciplinary Center | Houades V.,French National Center for Scientific Research | And 10 more authors.
Neuroscience | Year: 2015

Neurons and astrocytes, the two major cell populations in the adult brain, are characterized by their own mode of intercellular communication - the synapses and the gap junctions (GJ), respectively. In addition, there is increasing evidence for dynamic and metabolic neuroglial interactions resulting in the modulation of synaptic transmission at the so-called "tripartite synapse". Based on this, we have investigated at the ultrastructural level how excitatory synapses (ES) and astroglial GJ are spatially distributed in layer IV of the barrel cortex of the adult mouse. We used specific antibodies for connexin (Cx) 30 and 43 to identify astroglial GJ, these two proteins are known to be present in the majority of astroglial GJ in the cerebral cortex. In electron-microscopic images, we measured the distance between two ES, between two GJ and between a GJ and its nearest ES. We found a ratio of two GJ per three ES in the hollow and septal areas. Taking into account the size of an astrocyte domain, the high density of GJ suggests the occurrence of reflexive type, i.e. GJ between processes of the same astrocyte. Interestingly, the distance between an ES and an astroglial GJ was found to be significantly lower than that between either two synapses or between two GJ. These observations indicate that the two modes of cell-to-cell communication are not randomly distributed in layer IV of the barrel cortex. Consequently, this feature may provide the morphological support for the recently reported functional interactions between neuronal circuits and astroglial networks. © 2015 IBRO.


Harcha P.A.,University of Santiago de Chile | Harcha P.A.,Instituto Milenio | Vargas A.,University of Santiago de Chile | Yi C.,The Interdisciplinary Center | And 10 more authors.
Journal of Neuroscience | Year: 2015

Mast cells (MCs) store an array of proinflammatory mediators in secretory granules that are rapidly released upon activation by diverse conditions including amyloid beta (Aβ) peptides. In the present work, we found a rapid degranulation of cultured MCs through a pannexin1 hemichannel (Panx1 HC)-dependent mechanism induced by Aβ25–35 peptide. Accordingly, Aβ25–35 peptide also increased membrane current and permeability, as well as intracellular Ca2+ signal, mainly via Panx1 HCs because all of these responses were drastically inhibited by Panx1 HC blockers and absent in the MCs of Panx1−/− mice. Moreover, in acute coronal brain slices of control mice, Aβ25–35 peptide promoted both connexin 43 (Cx43)- and Panx1 HC-dependentMCdye uptake and histamine release, responses that were only Cx43 HC dependent in Panx1−/− mice. Because MCs have been found close to amyloid plaques of patients with Alzheimer’s disease (AD), their distribution in brain slices of APPswe/PS1dE9 mice, a murine model of AD, was also investigated. The number of MCs in hippocampal and cortical areas increased drastically even before amyloid plaque deposits became evident. Therefore, MCs might act as early sensors of amyloid peptide and recruit other cells to the neuroinflammatory response, thus playing a critical role in the onset and progression of AD. © 2015 the authors.

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