A study on the genetic contribution to microglial activation in schizophrenia (SCZ) used human induced pluripotent stem cell-derived microglia from monozygotic twins discordant for SCZ and healthy individuals to assess transcriptional and functional differences. Microglia from affected twins showed increased expression of inflammation-related genes and reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytic activity. Ingenuity Pathway Analysis (IPA) revealed abnormalities in extracellular matrix signaling, while RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and activation of the hepatic fibrosis pathway in both affected and unaffected twins. However, major histocompatibility complex (MHC) class II receptor upregulation was only observed in affected twin microglia. Affected twin microglia also showed heterogeneous responses to clozapine, minocycline, and sulforaphane treatments. Despite increased inflammatory gene expression, no clear functional signs of hyperactivation were observed in SCZ microglia. The study concluded that SCZ microglia have gene expression aberrations related to inflammation and extracellular matrix without contributing to increased microglial activation. The findings suggest that microglia from SCZ patients have genetic variations affecting inflammation and extracellular matrix, but not necessarily hyperactivation. The study also found that drug treatments like clozapine, minocycline, and sulforaphane had varied effects on SCZ microglia. The study highlights the importance of using patient-derived models to test potential treatments for SCZ and other mental disorders. Limitations include the rapid adaptation of microglia to environmental changes and potential masking of differences in microglial responses to inflammatory stimuli. The study emphasizes the need for further research with larger patient cohorts to validate findings. Data are available for RNA sequencing and pathway analysis.A study on the genetic contribution to microglial activation in schizophrenia (SCZ) used human induced pluripotent stem cell-derived microglia from monozygotic twins discordant for SCZ and healthy individuals to assess transcriptional and functional differences. Microglia from affected twins showed increased expression of inflammation-related genes and reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytic activity. Ingenuity Pathway Analysis (IPA) revealed abnormalities in extracellular matrix signaling, while RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and activation of the hepatic fibrosis pathway in both affected and unaffected twins. However, major histocompatibility complex (MHC) class II receptor upregulation was only observed in affected twin microglia. Affected twin microglia also showed heterogeneous responses to clozapine, minocycline, and sulforaphane treatments. Despite increased inflammatory gene expression, no clear functional signs of hyperactivation were observed in SCZ microglia. The study concluded that SCZ microglia have gene expression aberrations related to inflammation and extracellular matrix without contributing to increased microglial activation. The findings suggest that microglia from SCZ patients have genetic variations affecting inflammation and extracellular matrix, but not necessarily hyperactivation. The study also found that drug treatments like clozapine, minocycline, and sulforaphane had varied effects on SCZ microglia. The study highlights the importance of using patient-derived models to test potential treatments for SCZ and other mental disorders. Limitations include the rapid adaptation of microglia to environmental changes and potential masking of differences in microglial responses to inflammatory stimuli. The study emphasizes the need for further research with larger patient cohorts to validate findings. Data are available for RNA sequencing and pathway analysis.