Astrocyte gap junction dysfunction activates JAK2-STAT3 pathway to mediate inflammation in depression

Abstract

Connexin 43 (Cx43) is highly expressed in astrocytes and forms gap junctions that maintain intercellular communication. Dysfunctional gap junctions in astrocytes exacerbate depressive symptoms, which has been implicated in the pathogenesis of depression. Inflammatory responses occur in the brains of most people with depression. However, it is unclear whether dysfunctional astrocyte gap junctions mediate the onset of the inflammatory response in the brains of depressed patients. Transporter protein (TSPO), the most common neuroinflammatory marker and a novel target of antidepressants identified in recent years, is mainly expressed by glial cells in the brain and is abnormally upregulated during inflammatory activation. We found that in a mouse model of chronic unpredictable stress (CUS), astrocyte gap junctions in the prefrontal cortex are impaired and the JAK2-STAT3 signaling pathway is activated, leading to an increase in the inflammatory marker TSPO. Based on this finding, we further verified using Cx43 transgenic mice that conditional knockdown of Cx43 in prefrontal cortex astrocytes also activated the JAK2-STAT3 inflammatory signaling pathway, with concomitant elevated levels of the inflammatory marker TSPO, and the mice developed depressive-like behavior. In contrast, impaired corticosterone (CORT)-induced gap junction function and increased TSPO were ameliorated by the JAK2-STAT3 inhibitor protosappanin A (PTA). Thus, targeting astrocyte Cx43 attenuates the inflammatory response in depression and improves depressive symptoms. This provides a new perspective on the pathogenesis of depression and a new therapeutic target for antidepressant research.