The article "Microglia-neuron interactions in schizophrenia" by Hartmann et al. explores the complex interplay between microglia and neurons in the pathogenesis of schizophrenia spectrum disorders (SCSZ). Schizophrenia is a heterogeneous neuropsychiatric disorder characterized by positive, negative, and cognitive symptoms, with structural brain changes and altered neurotransmitter signaling. Microglia, the immune cells of the brain, play a crucial role in neuroinflammation and synaptic pruning, which are implicated in the development of SCSZ. - **Post-mortem Studies**: These studies provide insights into inflammatory processes and microglial alterations in SCSZ. Increased microglial density and morphology changes are observed in various brain regions, particularly in the prefrontal cortex. Satellite microglia, which interact directly with neurons, show reduced density and increased mitochondrial dysfunction in SCZ patients. - **Brain Imaging Studies**: Positron emission tomography (PET) imaging using tracers like 18-kDa translocator protein (TSPO) shows increased microglial activation in SCSZ patients, though results are mixed. Some studies report increased TSPO binding, while others show no significant changes. - **Body Fluids/Genetics**: Elevated peripheral markers of inflammation, such as IL-6 and CRP, are associated with symptom severity and cognitive impairment in SCZ. Genetic studies have identified risk factors, including variants in the complement component C4 gene, which is involved in synaptic pruning. - **Maternal Immune Activation (MIA) Models**: MIA models induce neuroinflammation and microglial activation in offspring, leading to behavioral abnormalities. Treatment with minocycline, an anti-inflammatory antibiotic, rescues microglial activation and neuronal phenotypes. - **Genetic Animal Models**: Overexpression of complement component C4 in mice models results in social behavior deficits, anxiety, and memory impairments, resembling SCZ symptoms. C4A overexpression is associated with increased synaptic pruning, contributing to synapse loss in SCZ. - **Advantages of Co-culture Models**: Co-culture models of iPSC-derived microglia and neurons allow for detailed examination of cell-cell interactions. Studies show that co-culturing microglia and neurons from healthy controls (HC) results in improved maturation and reduced inflammatory responses. - **Co-culturing Schizophrenia Neurons and Microglia**: Co-cultures of SCZ neurons and microglia reveal excessive synaptic loss and increased microglial engulfment of synaptic structures. RNA sequencing identifies upregulated immune-related transcripts in SCZ microglia, suggesting increased inflammation and inflammasome activation. - **Co-culturing Cortical Interneurons with Microglia**: Interneurons co-cultured with activated microglia exhibit metabolic deficits and upregulation of inflammatory genes, indicating a persistent inflammatory response. - **Methodological Limitations**: Post-mortem studies face challengesThe article "Microglia-neuron interactions in schizophrenia" by Hartmann et al. explores the complex interplay between microglia and neurons in the pathogenesis of schizophrenia spectrum disorders (SCSZ). Schizophrenia is a heterogeneous neuropsychiatric disorder characterized by positive, negative, and cognitive symptoms, with structural brain changes and altered neurotransmitter signaling. Microglia, the immune cells of the brain, play a crucial role in neuroinflammation and synaptic pruning, which are implicated in the development of SCSZ. - **Post-mortem Studies**: These studies provide insights into inflammatory processes and microglial alterations in SCSZ. Increased microglial density and morphology changes are observed in various brain regions, particularly in the prefrontal cortex. Satellite microglia, which interact directly with neurons, show reduced density and increased mitochondrial dysfunction in SCZ patients. - **Brain Imaging Studies**: Positron emission tomography (PET) imaging using tracers like 18-kDa translocator protein (TSPO) shows increased microglial activation in SCSZ patients, though results are mixed. Some studies report increased TSPO binding, while others show no significant changes. - **Body Fluids/Genetics**: Elevated peripheral markers of inflammation, such as IL-6 and CRP, are associated with symptom severity and cognitive impairment in SCZ. Genetic studies have identified risk factors, including variants in the complement component C4 gene, which is involved in synaptic pruning. - **Maternal Immune Activation (MIA) Models**: MIA models induce neuroinflammation and microglial activation in offspring, leading to behavioral abnormalities. Treatment with minocycline, an anti-inflammatory antibiotic, rescues microglial activation and neuronal phenotypes. - **Genetic Animal Models**: Overexpression of complement component C4 in mice models results in social behavior deficits, anxiety, and memory impairments, resembling SCZ symptoms. C4A overexpression is associated with increased synaptic pruning, contributing to synapse loss in SCZ. - **Advantages of Co-culture Models**: Co-culture models of iPSC-derived microglia and neurons allow for detailed examination of cell-cell interactions. Studies show that co-culturing microglia and neurons from healthy controls (HC) results in improved maturation and reduced inflammatory responses. - **Co-culturing Schizophrenia Neurons and Microglia**: Co-cultures of SCZ neurons and microglia reveal excessive synaptic loss and increased microglial engulfment of synaptic structures. RNA sequencing identifies upregulated immune-related transcripts in SCZ microglia, suggesting increased inflammation and inflammasome activation. - **Co-culturing Cortical Interneurons with Microglia**: Interneurons co-cultured with activated microglia exhibit metabolic deficits and upregulation of inflammatory genes, indicating a persistent inflammatory response. - **Methodological Limitations**: Post-mortem studies face challenges