Genetic contribution to microglial activation in schizophrenia.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Neuroinflammation is implicated in schizophrenia (SCZ) pathophysiology.
• Microglia, brain immune cells, play roles in neurogenesis and synaptic function.
• Aberrant microglial activation is a leading hypothesis in SCZ, but human cell models are lacking.

Purpose of the Study:

• To investigate transcriptional and functional differences in human induced pluripotent stem cell-derived microglia from SCZ patients and healthy individuals.
• To utilize monozygotic twins discordant for SCZ to model disease-specific microglial changes.
• To assess microglial responses to inflammatory stimuli and potential therapeutic agents.

Main Methods:

• Generation of human induced pluripotent stem cell-derived microglia from monozygotic twins discordant for SCZ and healthy controls.
• Transcriptional analysis using RNA sequencing and Ingenuity Pathway Analysis (IPA).
• Functional assays assessing response to interleukin-1 beta (IL1β), migration, phagocytosis, and drug treatments (clozapine, minocycline, sulforaphane).

Main Results:

• Microglia from affected twins exhibited increased expression of inflammation-related genes compared to controls.
• Reduced response to IL1β treatment was observed in affected twin microglia, with no significant differences in migration or phagocytosis.
• IPA revealed abnormalities in extracellular matrix signaling, with shared downregulation of ECM-related GO terms and hepatic fibrosis pathway activation in both affected and unaffected twins. Upregulation of MHC class II receptors was specific to affected twin microglia.

Conclusions:

• Schizophrenia patients' microglia display gene expression aberrations in inflammation and extracellular matrix pathways.
• Despite altered gene expression, clear signs of microglial hyperactivation were not observed.
• These findings suggest complex, non-hyperactivated roles for microglia in SCZ pathophysiology, potentially involving altered signaling pathways.