title: Activated microglia impairs neuroglial interaction by opening Cx43 hemichannels in hippocampal astrocytes.
abstract: 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.
authors: Collège de France, Center for Interdisciplinary Research in Biology (CIRB)/Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7241/Institut National de la Santé et de la Recherche Médicale U1050, Paris Cedex, France; University Pierre et Marie Curie, ED, Paris, France; MEMOLIFE Laboratory of Excellence and Paris Science Lettre Research University, Paris, France; Departamento de Fisiología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors: Verónica
authors: V
authors: Abudara
authors: Lisa
authors: L
authors: Roux
authors: Glenn
authors: G
authors: Dallérac
authors: Isabelle
authors: I
authors: Matias
authors: Jérôme
authors: J
authors: Dulong
authors: Jean Pierre
authors: JP
authors: Mothet
authors: Nathalie
authors: N
authors: Rouach
authors: Christian
authors: C
authors: Giaume
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D039481:CD11b Antigen / Q000378:metabolism; D002229:Carbenoxolone / Q000494:pharmacology; D000075302:Connexin 30; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D008911:Minocycline / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D039481:CD11b Antigen; D000075302:Connexin 30; D018031:Connexin 43; D017630:Connexins; D016207:Cytokines; C514423:Gap 26 peptide; C100629:Gjb6 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D010455:Peptides; D018698:Glutamic Acid; D008911:Minocycline; D002229:Carbenoxolone
keywords: astroglia; gap junctions; neuroinflammation