Figure 4.

Schematic representation of the potential link between the astroglial connexins and the response to venlafaxine. In line with the literature, chronic stress (modeled here by the long-term exposure to corticosterone, CORT) is believed to block astroglial gap junctions (GJs) while maintaining hemichannels (HCs) opened. This configuration generates a high level of anxiety and resignation (A) suggesting that the impairment of GJ is sufficient to induce a depressive-like phenotype regardless of the functional status of the HCs. On the contrary, the long-term treatment with the antidepressant venlafaxine, either in direct opposition to CORT or by direct modulation of Cx, increases GJ and decreases HC expression/function. This configuration is associated with a reduced level of anxiety and resignation (B). The addition of the Cx blocker carbenoxolone (CBX) attenuates the response to venlafaxine and increases the risk of relapse after treatment withdrawal. Although CBX is not selective to GJs or HCs, this effect could result from direct inhibitory action on GJs (purple arrow). An interaction between CBX and venlafaxine (or CORT) catabolism (hatched purple arrow) is not excluded (C). Figure created with BioRender.com.