Abstract
Glial cells, and in particular astrocytes, are crucial to maintain neuronal microenvironment by regulating energy metabolism, neurotransmitter uptake, gliotransmission, and synaptic development. Moreover, a typical feature of astrocytes is their high expression level of connexins, a family of membrane proteins that form gap junction channels allowing intercellular exchanges and hemichannels that provide release and uptake pathways for neuroactive molecules. Interestingly, several studies have revealed unexpected changes in astrocytes from depressive patients and rodent models of depressive-like behavior. Moreover, changes in the expression level of the astroglial connexin 43 (Cx43) have been reported in a depressive context. On the other hand, antidepressive drugs have also been shown to impact the expression of this connexin in astrocytes. However, so far there is little information concerning the functional consequence of these changes, i.e., the status of gap junctional communication and hemichannel activity in astrocytes exposed to antidepressants. In the present work we focused our attention on the action of seven antidepressants from four different therapeutic classes and tested their effects on Cx43 expression and on the two connexin-based channels functions studied in cultured astrocytes. We here report that when used at non-toxic and clinically relevant concentrations they have no effects on Cx43 expression but differential effects on Cx43 gap junction channels. Moreover, all tested antidepressants inhibit Cx43 hemichannel with different efficiency depending on their therapeutic classe. By studying the impact of antidepressants on the functional status of astroglial connexin channels, contributing to dynamic neuroglial interactions, our observations should help to better understand the mechanism by which these drugs provide their effect in the brain.
Highlights
During the two last decades, a major step in the understanding of brain functions and dysfunctions has been to consider that neurons are at the center of these processes but that their glial environment is actively involved
Cultured cortical astrocytes were treated with concentrations identical to those reported for brains of human or rodent after treatment with clinically relevant doses from in vivo studies: for fluoxetine, 20 μM in human brain is achieved at 20 mg/day; for venlafaxine, 10 μM in mice brain is reached at 20 mg/kg (Karlsson et al, 2011); for duloxetine, 4.2 mg/kg in rat leads to 10 μM in brain (Kielbasa and Stratford, 2012)
The first question addressed during this screening with antidepressants was their effect on the level of connexin 43 (Cx43) expression investigated by western blotting
Summary
During the two last decades, a major step in the understanding of brain functions and dysfunctions has been to consider that neurons are at the center of these processes but that their glial environment is actively involved. In brain pathologies and mental illness this partnership is impaired, contributing to severe neuronal defects and even in certain cases leading to neuronal death (Giaume et al, 2007; Bennett et al, 2012; Parpura et al, 2012) Such alterations in neuroglial interaction start to be investigated in order to identify and develop alternative therapeutic approaches that target astrocytes instead of solely neurons (Colangelo et al, 2014; Lundgaard et al, 2014; Vardjan et al, 2015). Following this strategy, the objective is to act on a specific astroglial molecular constituent known to regulate neuronal activity and/or survival. Much less is known about the status, i.e., expression and function, of Cxs in astrocytes in non-neurodegenerative mood disorders such as depression, while those pathologies are associated to a reduction in the number of astrocytes and a decrease in GFAP immunoreactivity (see Rajkowska and Stockmeier, 2013)
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