Defining functional states and roles of microglia in neuropsychiatric disorders

Microglia are myeloid cells of the central nervous system (CNS) that acquire a context-specific phenotype and adjust their functions to microenvironmental cues. They participate in immune signaling, synaptic remodeling, and circuit functions, and have emerged as key culprits in neurodevelopmental and psychiatric disorders such as depression, anxiety, autism spectrum disorder (ASD), and schizophrenia. We characterize and discuss different functional state of microglia defined by sc-omics approaches that bring a high resolution to cell functionalities. Subsequently, we review the evidence of microglial states, microglia-driven mechanisms and their impacts on development and progression of neuropsychiatric disorders. In affective mood disorders, chronic stress, glucocorticoid dysregulation, and peripheral inflammation drive microglial nefarious activation. This leads to excessive synaptic pruning, impaired neurotrophic support, glutamate excitotoxicity, and circuit dysfunction in mood-related brain regions, with strong modulation by circadian mechanisms and sex-dependent factors. In ASD, microglia adopt a hybrid activation state characterized by altered inflammatory signaling, dysregulated phagocytosis, and aberrant synaptic pruning, driven by genetic and epigenetic mechanisms, including TREM2, ARID1A, complement components, and calcium-dependent glial signaling, which together disrupt network connectivity and social behavior. In schizophrenia, genetic risk factors related to C4 and DISC1, along with inflammatory and metabolic stress, promote excessive microglia-mediated synapse elimination, cytoskeletal and motility deficits, and secondary neuronal metabolic dysfunction, which correlate with cognitive and negative symptoms. These findings strongly position microglia as a hub and key determinants of CNS homeostasis whose context-dependent dysregulation links immune, genetic, and environmental risk factors to synaptic and behavioral pathology. We discuss which microglial signaling pathways are shared and identify promising therapeutic targets across the neuropsychiatric disease spectrum.