Abstract
Depression is a major global public health issue. The recurrent episodes of depression and its unpredictable suicide risk have posed a critical medical challenge, highlighting the urgent need for an in-depth investigation into its underlying mechanisms. While the conventional hypothesis of monoamine neurotransmitter depletion is the primary cause of major depressive disorder (MDD), this theory does not entirely explain the complexity and clinical variability of MDD. The presence of treatment-resistant depression (TRD), as a subgroup of MDD, serves as compelling evidence. The immune-inflammation hypothesis has gained increasing attention, with a growing focus on the pivotal role of microglia in this framework. Microglia, the resident immune cells of the central nervous system, sustain homeostasis through self-renewal in adulthood. They are essential for regulating neuron survival, apoptosis, and synaptic plasticity under normal physiological conditions. Under pathological situations, such as traumatic injury, infection, and psychological stress, microglia receive stimulating signals to promptly respond to events. When microglia homeostasis is disrupted, they become over-activated, releasing pro-inflammatory cytokines, activating related signaling pathways, and disrupting neurotransmitter metabolism. This triggers neuroinflammation, oxidative stress, and mitochondrial dysfunction, which hinder neurogenesis, disrupt neural circuits, and ultimately contribute to MDD progression, or even potentially advance it to TRD. This review focuses on the relationship between the biology of microglia and MDD, providing a comprehensive analysis of microglial biological characteristics, factors affecting microglia function, and underlying mechanisms associated with MDD. In conclusion, this review provides a novel perspective on the pathogenesis of MDD from the angle of microglial homeostasis imbalance, aiming to lay a theoretical basis for subsequent investigation of the mechanism. In addition, based on the mechanism of neuroinflammation caused by microglial homeostasis imbalance in MDD, this review aims to offer two new promising therapeutic approaches for MDD and even its progression to the TRD stage.