PDE4 inhibition alleviates HMGB1/C1q/C3-mediated excessive phagocytic pruning of synapses by microglia and depressive-like behaviors in mice.

Microglial activation and complement-mediated synaptic pruning are involved in depression development. We previously found that the inhibition of phosphodiesterase 4 (PDE4) inhibits microglial activation and increases synaptic plasticity. However, the role of PDE4 in microglia phagocytosis and complement-mediated synaptic pruning during depression remains unclear. Here, we investigated the effect of PDE4 on the expression of complement component 1q (C1q) and C3. We also designed and synthesized a novel PDE4 inhibitor LS21013A-06 (A06), and examined whether A06 exerts antidepressant-like effects by regulating microglia phagocytosis and complement-mediated synaptic pruning. We found that treatment with high-mobility group box-1 (HMGB1) triggered an inflammatory response, enhanced levels of complement component 1q (C1q) and C3, and promoted microglial phagocytosis both in vitro and in vivo. Notably, PDE4B knockdown reduced the levels of HMGB1, C1q, and C3 in lipopolysaccharide (LPS)-treated BV2 cells. Inhibition of PDE4 by A06 reduced the levels of HMGB1, suppressed neuroinflammation and microglial phagocytosis. In addition, A06 alleviated LPS-induced depressive-like behaviors in mice, reduced the levels of HMGB1, C1q, and C3 in the hippocampus, elevated the level of postsynaptic density protein-95, and reduced excessive microglial phagocytosis and engulfment of synapses. Moreover, C1q overexpression inhibited the effects of A06 on microglial activation and synaptic pruning. In conclusion, we demonstrated for the first time that PDE4 regulates the expression of C1q/C3, and A06 reduces microglial activation and ameliorates depressive-like behavior in mice. This mechanism involves complement C1q/C3-mediated excessive microglia phagocytosis and synaptic pruning.