The pathogenesis of depression: Roles of connexin 43-based gap junctions and inflammation.

Abstract

Background: Depression is a leading chronic mental illness worldwide, characterized by anhedonia and pessimism. Connexin is a kind of widely distributed protein in the body. Connexin 43 (Cx43) plays an important role in the pathogenesis of depression. Growing evidence has indicated that inflammation is closely associated with neuropsychiatric diseases such as depression. Inflammation occurs in patients with mood disorders, and symptomatic relief after multiple treatments is often accompanied by proinflammatory restoration. In this study, we sought to determine the upstream and downstream relationship of Cx43 abnormalities and peripheral inflammation in inducing depression.

Methods and results: Gap27, as a Cx43 mimetic peptide, specifically blocks Cx43 gap junction channels in the brain. The mice were treated with injection of Gap27 into the prefrontal cortex (PFC), conditional knockout of Cx43 in the PFC, and lipopolysaccharide (LPS) intraperitoneal injection. Our results revealed that the treatments gave rise to the depressive-like behavior occurrence in mice, including reducing the sucrose preference and spontaneous activities, and increasing immobility time in the forced swimming test. Functional blockade of Cx43 induced abnormal expression of peripheral inflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, IL-2, IL-10, and IL-18. Furthermore, depression associated with peripheral inflammation derived from LPS intraperitoneal injection significantly reduced the Cx43 expression and the diffusion distance of gap junction channel permeability dye in the PFC.

Conclusion: These results showed that blockade of Cx43 in the PFC and peripheral inflammation are complicatedly intertwined, and reinforcing each other during the induction of depression.