Activation of the C3 Complement Pathway in the Hippocampus Produces Anxiodepressive Effects in a Mouse Model of Inflammation Pain

Mol Neurobiol. 2025 Jul 11. doi: 10.1007/s12035-025-05187-8. Online ahead of print.

ABSTRACT

The comorbidity of anxiety and depression frequently occurs in patients with inflammatory pain, which requires further investigation. Previous evidence supports a close link between Complement Component 3 (C3) and affective disorders; however, whether C3 is involved in inflammatory pain-induced anxiodepression remains unclear. Using a mouse inflammatory pain model with Complete Freund’s Adjuvant (CFA), we observed that the animals exhibited significant anxiodepression-like behaviors and that the expression of hippocampal C3 was obviously increased three weeks after CFA injection. Microinjection of the AAV vector that downregulates C3 into the hippocampus alleviated anxiodepression-like behaviors. Moreover, we noted that knocking down hippocampal C3 partially alleviated pain behavior in CFA-treated mice. Mechanistically, we found that the benefit of knocking down the hippocampal C3 may be due to inhibition of its downstream C3aR-GSK3β signaling pathway and restoration of glia activation and inflammatory response to levels similar to those found under non-inflammatory conditions. Consequently, our work reveals the critical role of the hippocampal C3/C3aR-GSK3β signaling pathway in inflammatory pain-induced anxiodepression-like behaviors, suggesting that C3/C3aR-GSK3β signaling is a potential therapeutic target for inflammatory pain-induced mental health conditions.

PMID:40646411 | DOI:10.1007/s12035-025-05187-8