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Activation of the C3 Complement Pathway in the Hippocampus Produces Anxiodepressive Effects in a Mouse Model of
Aomei Zhang1, Xinxin Zhang1, Xiaohan Tang1
1Clinical Anatomy & Reproductive Medicine Application Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
Insights
Complement Component 3 (C3) in the hippocampus plays a key role in anxiety and depression linked to inflammatory pain. Targeting the C3/C3aR-GSK3β pathway may offer new treatments for these conditions.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Anxiety and depression commonly co-occur with inflammatory pain.
- A link exists between Complement Component 3 (C3) and affective disorders, but its role in inflammatory pain-induced anxiodepression is unknown.
Purpose of the Study:
- To investigate the role of hippocampal C3 in inflammatory pain-induced anxiodepression.
- To explore the underlying molecular mechanisms involving the C3aR-GSK3β pathway.
Main Methods:
- A mouse model of inflammatory pain was induced using Complete Freund's Adjuvant (CFA).
- Hippocampal C3 expression was measured, and its levels were modulated using AAV vectors.
- Anxiodepression-like behaviors and pain behaviors were assessed.
- The C3aR-GSK3β signaling pathway, glia activation, and inflammatory responses were analyzed.
Main Results:
- CFA injection led to increased hippocampal C3 expression and anxiodepression-like behaviors in mice.
- Downregulating hippocampal C3 with AAV vectors alleviated these behaviors.
- Reducing hippocampal C3 also partially mitigated pain behavior.
- These effects were associated with the inhibition of the C3aR-GSK3β pathway and reduced glia activation.
Conclusions:
- The hippocampal C3/C3aR-GSK3β signaling pathway is critically involved in inflammatory pain-induced anxiodepression.
- C3 represents a potential therapeutic target for managing mental health issues associated with inflammatory pain.
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.
