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The central role of microglia in major depressive disorder and its potential as a therapeutic target
Xue Xia1, Kaiqing Li1, Wei Zou2
1Department of Graduate School of Heilongjiang University of Chinese Medicine, Harbin, China.
Abstract:
Major depressive disorder (MDD) is a complex neuropsychiatric condition whose multifactorial etiology remains incompletely explained by neuron-centric and neurotransmitter hypotheses alone. This review addresses that gap by positioning microglia-the CNS's resident immune cells-as central drivers of MDD pathogenesis. We organize current evidence around five interrelated themes: hypothalamic-pituitary-adrenal (HPA) axis dysfunction, monoaminergic and kynurenine pathway imbalances, neuroinflammatory overactivation, synaptic and white-matter integrity disruption, and gut-brain axis perturbations. In MDD, microglia shift from a surveillant resting state to either an overactivated or functionally inhibited phenotype, exacerbating pathology via aberrant cytokine release, dysregulated synaptic pruning and impaired myelin support. These changes are modulated by genetic susceptibility, sex differences, environmental stressors and microbiome alterations. We then survey translational advances-traditional and novel therapeutics that modulate microglial polarization, emerging blood- and imaging-based biomarkers, and strategies to harness microglia-oligodendrocyte cross-talk for remyelination-and highlight integrative platforms for stratifying inflammation-driven versus non-inflammatory subtypes. Our principal takeaway is that microglia represent a unifying nexus and actionable target for precision interventions tailored to individual biological profiles.
Insights
Microglia, the brain's immune cells, are key drivers of major depressive disorder (MDD). Targeting these cells offers new precision treatments for MDD, moving beyond traditional neurotransmitter hypotheses.
Area of Science:
- Neuroimmunology
- Neuropsychiatry
- Cellular Biology
Background:
- Major depressive disorder (MDD) etiology is complex, not fully explained by neuron-centric or neurotransmitter models.
- Microglia, the central nervous system's resident immune cells, are increasingly implicated in neuropsychiatric conditions.
- Existing hypotheses fail to fully account for the multifactorial nature of MDD.
Purpose of the Study:
- To review evidence positioning microglia as central drivers of MDD pathogenesis.
- To explore the interplay between microglial dysfunction and MDD-related biological pathways.
- To survey translational advances and therapeutic targets related to microglial modulation in MDD.
Main Methods:
- Literature review organizing evidence around five key themes: HPA axis, monoaminergic/kynurenine pathways, neuroinflammation, synaptic/white matter integrity, and gut-brain axis.
- Analysis of microglial phenotypic shifts (overactivated or inhibited) in MDD.
- Survey of therapeutic strategies, biomarkers, and diagnostic platforms.
Main Results:
- Microglia dysfunction, characterized by aberrant cytokine release and impaired synaptic/myelin support, exacerbates MDD pathology.
- MDD-related microglial changes are influenced by genetic, sex, environmental, and microbiome factors.
- Translational advances include therapeutics targeting microglial polarization and remyelination strategies.
Conclusions:
- Microglia represent a unifying nexus in MDD pathogenesis, offering actionable targets for precision interventions.
- Stratifying MDD subtypes based on inflammatory profiles is crucial for tailored treatment.
- Future research should focus on harnessing microglia-oligodendrocyte interactions for therapeutic benefit.
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