title: Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice.
abstract: Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs)-dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock-down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression-like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORT also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1178 - Dépression, Plasticité and Résistance Aux Antidépresseurs, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Université Paris-Sud Châtenay-Malabry, France.
authors.forename: Gaël
authors.initials: G
authors.lastname: Quesseveur
authors.affiliation: Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale UMR 5169, Centre de Biologie Intégrative, Université Toulouse III- Paul Sabatier Toulouse, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Portal
authors.affiliation: Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale UMR 5169, Centre de Biologie Intégrative, Université Toulouse III- Paul Sabatier Toulouse, France.
authors.forename: Jean-Arnaud
authors.initials: JA
authors.lastname: Basile
authors.affiliation: Center for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, Collège de France Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Ezan
authors.affiliation: Centre des Sciences du Goût et de l'Alimentation - Centre National de la Recherche Scientifique UMR 6265 - Institut National de la Recherche Agronomique UMR 1324, Université de Bourgogne Dijon, France.
authors.forename: Alexia
authors.initials: A
authors.lastname: Mathou
authors.affiliation: Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale UMR 5169, Centre de Biologie Intégrative, Université Toulouse III- Paul Sabatier Toulouse, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Halley
authors.affiliation: Centre des Sciences du Goût et de l'Alimentation - Centre National de la Recherche Scientifique UMR 6265 - Institut National de la Recherche Agronomique UMR 1324, Université de Bourgogne Dijon, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Leloup
authors.affiliation: Centre des Sciences du Goût et de l'Alimentation - Centre National de la Recherche Scientifique UMR 6265 - Institut National de la Recherche Agronomique UMR 1324, Université de Bourgogne Dijon, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fioramonti
authors.affiliation: Laboratory of Cellular and Molecular Neurotherapies, Department of Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.affiliation: Center for Interdisciplinary Research in Biology, Centre National de la Recherche Scientifique UMR 7241, Collège de France Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Giaume
authors.affiliation: Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale UMR 5169, Centre de Biologie Intégrative, Université Toulouse III- Paul Sabatier Toulouse, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Rampon
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S 1178 - Dépression, Plasticité and Résistance Aux Antidépresseurs, Laboratoire de Neuropharmacologie EA 3544, Faculté de Pharmacie, Université Paris-SudChâtenay-Malabry, France; Centre National de la Recherche Scientifique, Centre de Recherches sur la Cognition Animale UMR 5169, Centre de Biologie Intégrative, Université Toulouse III- Paul SabatierToulouse, France.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
keywords: antidepressants; anxiety; astrocytes; behavior; connexin 43; depression; hippocampus; stress