Trans-cinnamaldehyde alleviates IFN-α-induced depressive-like behaviors by restoring astrocytic Cx43 gap junction

Interferon-alpha (IFN-α)-induced depression lacks effective treatments, and its neuroinflammatory mechanisms remain unresolved. Trans-cinnamaldehyde (TCA), a cinnamon-derived bioactive compound with anti-inflammatory properties, was investigated for its antidepressant potential in an IFN-α-induced murine depression model. Behavioral tests, fMRI, and electrophysiology revealed that TCA dose-dependently alleviated depressive-like behaviors, restored functional connectivity (mPFC-DMN-Hb), and enhanced mPFC neuronal excitability. Mechanistically, TCA downregulated phosphorylated connexin 43 (Cx43) in astrocytes while preserving total Cx43 expression, suppressed COX-2/NF-κB signaling, and reduced proinflammatory cytokines (IL-6, TNF-α) in the mPFC. Crucially, astrocyte-specific Cx43 knockout (Gfap-Cre; Cx43^fl/fl) mice exhibited depression-like phenotypes and hyperactivated neuroinflammation, abolishing TCA's therapeutic effects. These results demonstrate that TCA mitigates IFN-α-induced depression by modulating astrocytic Cx43 gap junctions and inhibiting COX-2/NF-κB-driven neuroinflammation, positioning it as a novel immunopharmacological agent for inflammation-associated depression and highlighting Cx43 as a potential therapeutic target.