Connexin 43: insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy

Major depressive disorder (MDD), a chronic and recurrent disease characterized by anhedonia, pessimism or even suicidal thought, remains a major chronic mental concern worldwide. Connexin 43 (Cx43) is the most abundant connexin expressed in astrocytes and forms the gap junction channels (GJCs) between astrocytes, the most abundant and functional glial cells in the brain. Astrocytes regulate neurons’ synaptic strength and function by expressing receptors and regulating various neurotransmitters. Astrocyte dysfunction causes synaptic abnormalities, which are related to various mood disorders, e.g., depression. Increasing evidence suggests a crucial role of Cx43 in the pathogenesis of depression. Depression down-regulates Cx43 expression in humans and rats, and dysfunction of Cx43 also induces depressive behaviors in rats and mice. Recently Cx43 has received considerable critical attention and is highly implicated in the onset of depression. However, the pathological mechanisms of depression-like behavior associated with Cx43 still remain ambiguous. In this review we summarize the recent progress regarding the underlying mechanisms of Cx43 in the etiology of depression-like behaviors including gliotransmission, metabolic disorders, and neuroinflammation. We also discuss the effects of antidepressants (monoamine antidepressants and ketamine) on Cx43. The clarity of the candidate pathological mechanisms of depression-like behaviors associated with Cx43 and its potential pharmacological roles for antidepressants will benefit the exploration of a novel antidepressant target.