Targeting the microglia-synapse interface in depression: molecular mechanisms and pharmacological perspectives from traditional Chinese medicine

Depression is a prevalent neuropsychiatric disorder characterized by impaired synaptic plasticity, disrupted neural circuits, and persistent neuroimmune dysregulation. Increasing evidence indicates that microglia-mediated synaptic pruning, a physiological process essential for neural circuit refinement, becomes abnormally activated under depressive conditions, leading to excessive synaptic elimination and impaired connectivity. Complement-dependent pathways, inflammatory signaling, mitochondrial dysfunction, and alterations in the neural microenvironment contribute to microglial activation and synaptic remodeling. Traditional Chinese Medicine (TCM), with its multi-component and multi-target properties, has shown potential antidepressant effects by regulating neuroinflammation, immune homeostasis, and synaptic plasticity. This review summarizes recent advances in microglia-mediated synaptic pruning in depression and discusses the potential role of TCM interventions in this neuroimmune pathway. Current studies suggest that stress-induced microenvironmental changes promote microglial activation and excessive synaptic engulfment, while TCM formulas, herbal extracts, and bioactive compounds may restore synaptic function by modulating microglial polarization, inflammatory responses, complement signaling, and mitochondrial homeostasis. However, direct evidence demonstrating the regulation of microglia-mediated synaptic pruning by TCM remains limited. Future research integrating single-cell sequencing, advanced imaging, and molecular tracing approaches is required to clarify these mechanisms. Overall, targeting microglial synaptic remodeling provides a promising framework for understanding depression pathogenesis and developing novel TCM-based therapeutic strategies.