Connexin 43: An Interface Connecting Neuroinflammation to Depression

Abstract

Major depressive disorder (MDD) is a leading chronic mental illness worldwide, characterized by anhedonia, pessimism and even suicidal thoughts. Connexin 43 (Cx43), mainly distributed in astrocytes of the brain, is by far the most widely and ubiquitously expressed connexin in almost all vital organs. Cx43 forms gap junction channels in the brain, which mediate energy exchange and effectively maintain physiological homeostasis. Increasing evidence suggests the crucial role of Cx43 in the pathogenesis of MDD. Neuroinflammation is one of the most common pathological features of the central nervous system dysfunctions. Inflammatory factors are abnormally elevated in patients with depression and are closely related to nearly all links of depression. After activating the inflammatory pathway in the brain, the release and uptake of glutamate and adenosine triphosphate, through Cx43 in the synaptic cleft, would be affected. In this review, we have summarized the association between Cx43 and neuroinflammation, the cornerstones linking inflammation and depression, and Cx43 abnormalities in depression. We also discuss the significant association of Cx43 in inflammation and depression, which will help to explore new antidepressant drug targets.

Investigating the Impact of SN-38 on Mouse Brain Metabolism Based on Metabolomics

“…Brain endothelial cells exposed to high levels of glutamate activate N-methyl-D-aspartate receptors, disrupting the blood-brain barrier. 28 Aspartate, a non-essential amino acid, exhibits abnormal levels in various neurological disorders. 29 It affects glycolysis via the malate-aspartate shuttle, disrupting brain energy metabolism.…”

Exploring Astrocyte-Mediated Mechanisms in Sleep Disorders and Comorbidity

“…Studies have demonstrated that inhibition of connexin 43 exacerbates depressionlike behavior [180]. Supporting these findings, further research has indicated that the gap junction channels of astrocytes could potentially serve as targets for new antidepressant drug development [181,182]. Approaches such as enhancing astrocytic lactate production or promoting lactate uptake by neurons could potentially restore energy balance, improve sleep quality, and ameliorate comorbid conditions.…”

Connexin 43 Phosphorylation: Implications in Multiple Diseases

“…According to the literature, there are two possible theories: GJIC is thought to be critical for maintaining tissue homeostasis and propagating electrical and metabolic signals in cell populations [60]. Consistent with this, GJs can suppress seizure activity by redistributing K + and glutamate (Glu) [61][62][63][64][65]. Astrocytes are electrically and metabolically connected to each other through gap junctions mainly composed of Cx43 and Cx30, forming a functional network [66,67].…”

“…These studies suggest that the gap junction uncoupling process in astrocytes is intermediate between the phosphorylation and dephosphorylation of Cx43 and may be the result of Cx43 phosphorylation and the cause of hemichannel Cx43 dephosphorylation. Furthermore, hemichannel opening induced by Cx43 dephosphorylation in astrocytes promotes the release of inflammatory mediators and increases neuroinflammation after ischemic stroke [ 65 , 83 ]. In ischemic stroke, the phosphorylation of astrocyte Cx43 may lead to the uncoupling of gap junctions between astrocytes and other parenchymal cells, thereby reducing the direct communication between these cells.…”