Microglia-neuron interactions in schizophrenia: A review. Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with increased neuroinflammation, particularly involving microglia. Microglia, the primary innate immune cells of the brain, play a crucial role in synaptic pruning during brain development and synaptic plasticity in adulthood. In SCZ, genetic and environmental risk factors may lead to increased microglial activation, elevated pro-inflammatory cytokines, and inflammasome activation, contributing to an overall neuroinflammatory state. Synaptic loss, a key pathological feature of SCZ, is believed to result from excessive synaptic pruning by activated microglia, primarily affecting glutamatergic neurons. Research has investigated microglia-neuron interactions using post-mortem brain tissues, brain imaging, animal models, and patient-derived iPSC cultures. This review summarizes findings from these studies and discusses the potential of anti-inflammatory treatments for alleviating positive, negative, and cognitive symptoms of SCZ. Microglia are involved in synaptic pruning, a process mediated by the complement system, including components such as C1q, C4, and C3. In SCZ, genetic risk factors or early insults, such as maternal infection, may prime microglia, making them more susceptible to stressors later in life. This can lead to aberrant synaptic pruning and contribute to the development of SCZ. Post-mortem studies have shown increased microglial density in certain brain regions of SCZ patients, while molecular studies have identified altered inflammatory signaling and immune-related gene expression in SCZ. Brain imaging studies using PET have shown increased microglial activation in SCZ patients, particularly in the prefrontal cortex. Additionally, studies of body fluids and genetics have revealed associations between inflammatory markers and SCZ, suggesting a role for inflammation in the disease. Animal models of SCZ, including maternal immune activation (MIA) models and genetic models, have been used to study microglia-neuron interactions. MIA models, which mimic prenatal immune challenges, have shown increased microglial activation and altered neuronal phenotypes in offspring. Genetic models, such as those involving complement component C4, have also been used to investigate synaptic pruning and its role in SCZ. iPSC-derived models have provided insights into microglia-neuron interactions in SCZ, revealing excessive synaptic pruning and altered inflammatory responses. Co-culturing SCZ-derived neurons and microglia has shown increased synaptic engulfment and activation of the inflammasome pathway, suggesting a role for microglial activation in the disease. Anti-inflammatory treatments, such as minocycline, have shown potential in reducing microglial activation and synaptic pruning in SCZ models. However, the effectiveness of these treatments in human studies remains limited, highlighting the need for more detailed clinical stratification. Overall, microglia-neuron interactions are a critical area of research in SCZ, with implications forMicroglia-neuron interactions in schizophrenia: A review. Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with increased neuroinflammation, particularly involving microglia. Microglia, the primary innate immune cells of the brain, play a crucial role in synaptic pruning during brain development and synaptic plasticity in adulthood. In SCZ, genetic and environmental risk factors may lead to increased microglial activation, elevated pro-inflammatory cytokines, and inflammasome activation, contributing to an overall neuroinflammatory state. Synaptic loss, a key pathological feature of SCZ, is believed to result from excessive synaptic pruning by activated microglia, primarily affecting glutamatergic neurons. Research has investigated microglia-neuron interactions using post-mortem brain tissues, brain imaging, animal models, and patient-derived iPSC cultures. This review summarizes findings from these studies and discusses the potential of anti-inflammatory treatments for alleviating positive, negative, and cognitive symptoms of SCZ. Microglia are involved in synaptic pruning, a process mediated by the complement system, including components such as C1q, C4, and C3. In SCZ, genetic risk factors or early insults, such as maternal infection, may prime microglia, making them more susceptible to stressors later in life. This can lead to aberrant synaptic pruning and contribute to the development of SCZ. Post-mortem studies have shown increased microglial density in certain brain regions of SCZ patients, while molecular studies have identified altered inflammatory signaling and immune-related gene expression in SCZ. Brain imaging studies using PET have shown increased microglial activation in SCZ patients, particularly in the prefrontal cortex. Additionally, studies of body fluids and genetics have revealed associations between inflammatory markers and SCZ, suggesting a role for inflammation in the disease. Animal models of SCZ, including maternal immune activation (MIA) models and genetic models, have been used to study microglia-neuron interactions. MIA models, which mimic prenatal immune challenges, have shown increased microglial activation and altered neuronal phenotypes in offspring. Genetic models, such as those involving complement component C4, have also been used to investigate synaptic pruning and its role in SCZ. iPSC-derived models have provided insights into microglia-neuron interactions in SCZ, revealing excessive synaptic pruning and altered inflammatory responses. Co-culturing SCZ-derived neurons and microglia has shown increased synaptic engulfment and activation of the inflammasome pathway, suggesting a role for microglial activation in the disease. Anti-inflammatory treatments, such as minocycline, have shown potential in reducing microglial activation and synaptic pruning in SCZ models. However, the effectiveness of these treatments in human studies remains limited, highlighting the need for more detailed clinical stratification. Overall, microglia-neuron interactions are a critical area of research in SCZ, with implications for