Microglia, the resident immune cells of the central nervous system, are increasingly recognized as key regulators of neural development, synaptic plasticity, and behavior. In addition to their classical role in immune surveillance, microglia actively shape neuronal circuits and influence cognitive and emotional functions across the life span. Accumulating evidence now implicates aberrant or chronic microglial activation as a central mechanism underlying neuroinflammation-associated behavioral and cognitive disturbances in a wide range of neuropsychiatric disorders, including major depressive disorder, schizophrenia, autism spectrum disorder, posttraumatic stress disorder, and attention-deficit/hyperactivity disorder. This narrative review synthesizes preclinical and clinical findings linking dysregulated microglial activation to brain pathology of neuropsychiatric disorders, with particular emphasis on cytokine signaling, oxidative stress, synaptic remodeling, and gut–brain–microglia interactions. This review discusses how sustained microglial priming and excessive inflammatory responses disrupt neurotransmitter systems, impair synaptic integrity, and alter neural network connectivity in brain regions critical for emotion regulation, cognition, and social behavior. Advances in neuroimaging, including TSPO-PET and multimodal approaches, have enabled in vivo assessment of microglial activation in humans, strengthening translational relevance. Furthermore, this review evaluates emerging therapeutic strategies aimed at modulating microglial function, including pharmacological immunomodulators, CSF1R-based depletion and repopulation approaches, lifestyle interventions, and novel cell-based and vesicle-based therapies. Finally, this review highlights key translational challenges, particularly species-specific differences between mouse and human microglia, and proposes future directions for precision neuroimmune interventions. Collectively, the evidence reviewed here positions microglia as both mechanistic drivers and therapeutic targets in neuropsychiatric disorders rooted in chronic neuroinflammation.
Uddin et al. (Mon,) studied this question.