Antidepressants Impact Connexin 43 Channel Functions in Astrocytes

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.

Potentiation of Amitriptyline Anti-Hyperalgesic-Like Action By Astroglial Connexin 43 Inhibition in Neuropathic Rats

“…Interestingly, this effect, also related to down regulation of Cx43 expression, occurred at therapeutic μM concentrations reached in humans45. Recently, a similar inhibitory effect of GJCs by amitriptyline was reported in mouse cultured astrocytes8. In contrast, Morioka et al 28.…”

“…Available treatments with anticonvulsants, antidepressants, opioids, and lidocaine or capsaicin patches are only moderately effective and may induce poorly tolerated side effects that negatively impact compliance12345. Numerous peripheral and central pathways have been suggested as new therapeutic avenues6; this study focused on a recently proposed target, astroglial connexins (Cxs), since these “gap junction proteins” have been reported to be involved in neuropathic pain7 and as a target for antidepressants8.…”

“…Contribution of this signaling sequence to pain sensitization mechanisms is supported by data showing that inactivation of Cx43-mediated functions by pharmacological202425 or genetic approaches26 reduces hyperalgesia-and allodynia-like behaviours in validated models of neuropathic pain. Furthermore, antidepressants used to alleviate neuropathic pain, such as duloxetine27 and amitriptyline28, were reported to affect Cx43 expression and function in astrocytes8.…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…In order to isolate the effects of specific drugs on astrocytes, many of these studies have been carried out in purified cell culture models, which removes the interaction between other brain cell types. There appears to be an overall consensus that treating astrocytes with SSRIs, such as fluoxetine, leads to increased expression of gap‐junction channel proteins in cultures (Jeanson et al, ; Mostafavi et al, ) as well as in vivo with chronic fluoxetine treatment (Fatemi et al, ). This has also been shown in cultured astrocytes treated with amitriptyline, a tricyclic antidepressant (Morioka et al, ).…”

Connexins in health and disease

“…In a functional study made in cortical and striatal mouse astroglia, antidepressants were shown to exert different effects on Cx43 gap junctions and hemichannel activities. These antidepressants inhibited Cx43 hemichannels . Pro‐inflammatory cytokines (tumor necrosis factor‐α and interleukin‐1β), which are released from activated microglia, open Cx43 hemichannels and this might be related to a major depressive disorders mechanism .…”