Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice.

Gaël Quesseveur,Bruno P Guiard,Pascal Ezan,Christian Giaume,Xavier Fioramonti,Corinne Leloup,Claire Rampon,Hélène Halley,Nicole Déglon,Benjamin Portal,Jean-Arnaud Basile,Alexia Mathou

doi:10.3389/fncel.2015.00490

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.

Highlights

Major depression (MD) is one of the most common mental disorders, affecting 350 million people worldwide and is a leading cause of disability (Milanovic et al, 2015)
As previously shown (Theis et al, 2003; Unger et al, 2012), we observed that Cx43fl/fl mice themselves displayed a dramatic decrease in the expression of Cx43 relative to control Cx43wt/wt mice in various brain regions including the hippocampus (∼−95%; t1,11 < 0.001) and the hypothalamus
The influence of antidepressant drugs on Cx43 expression is well described, little is known about the effects of these treatments on the functional status of Cx43 gap junction channels (GJCs) and Cx43 HC

Summary

Introduction

Major depression (MD) is one of the most common mental disorders, affecting 350 million people worldwide and is a leading cause of disability (Milanovic et al, 2015). MD imposes substantial economic costs and its impact on disability, productivity, and quality of life further accentuates these costs (Lecrubier, 2001). Selective serotonin reuptake inhibitors (SSRIs) represent the most widely prescribed class of antidepressant drugs, but approximately 50% of depressed patients do not respond adequately to SSRI. The onset of therapeutic action is of 2–4 weeks (Blier, 2001). Considering the prevalence of MD and its consequences on life’s quality, a better knowledge of its pathophysiology is required to envision the identification of new therapeutic targets

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