Targeting complement C3 with Tanshinone I decreases microglia-mediated synaptic engulfment to exert antidepressant...

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Current depression treatments have limitations, necessitating novel therapeutic strategies.
• Tanshinone I (Tan I), a natural compound, exhibits anti-inflammatory, anti-oxidative, and cell death-modulating properties.
• The antidepressant potential and underlying mechanisms of Tan I remain largely unexplored.

Purpose of the Study:

• To investigate the antidepressant effects of Tanshinone I (Tan I).
• To elucidate the mechanism of action of Tan I, focusing on microglia-mediated synaptic processes and brain network changes.
• To identify the specific molecular target of Tan I.

Main Methods:

• Animal models: Chronic unpredictable stress (CUS) mice and C3 overexpressing mice.
• Behavioral tests to assess antidepressant effects.
• Assays for target identification (drug affinity responsive target stability, microscale thermophoresis).
• Functional magnetic resonance imaging (fMRI) to evaluate brain network changes.
• Histological analysis to assess synaptic loss and microglial activation.

Main Results:

• Tan I significantly improved depressive-like behaviors in CUS mice, reduced synaptic loss, and inhibited microglial activation.
• Tan I directly binds to complement C3 (C3), acting as a C3 modulator.
• Tan I inhibited C3 deposition on synapses and subsequent microglia-mediated synaptic engulfment, improving fMRI-based network changes.
• C3 overexpression induced depressive-like behaviors, synaptic loss, and altered network activity, which were ameliorated by Tan I treatment.

Conclusions:

• Tan I demonstrates potent antidepressant effects by directly modulating complement C3 (C3).
• Tan I blocks the C3-CR3 axis and STAT3 signaling, inhibiting microglia-mediated synaptic pruning.
• Tan I improves brain network function and ameliorates depressive behaviors, presenting a promising natural therapeutic agent for depression.