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Schizophrenia is a complex mental health disorder that affects approximately 24 million people worldwide. Understanding the mechanisms that cause schizophrenia and developing effective treatments has been challenging due to the variability in how the disease presents. In a new study published in Science, researchers from McLean Hospital conducted comprehensive genetic and cellular analyses to gain insights into the molecular mechanisms underlying schizophrenia. By examining postmortem brain tissue from 140 individuals, the researchers identified specific cell types in the brain that express genes associated with schizophrenia risk differently, shedding light on how these genes impact biological functions within those cells.

The researchers found that excitatory neurons were the most affected cell group in individuals with schizophrenia, with transcriptional changes implicating neurodevelopment and synapse-related pathways. They also discovered that known genetic risk factors for schizophrenia converge on alterations in specific neuronal populations, highlighting the interplay between rare and common genomic variants. By analyzing more than 468,000 cells, the researchers were able to identify two distinct subpopulations of individuals with schizophrenia based on the expression of specific excitatory and inhibitory neuronal cell states. These findings provide a better understanding of the cellular basis of schizophrenia and lay the groundwork for future targeted interventions and personalized treatments.

The study suggests potential links between schizophrenia pathology and processes such as neurodevelopment, synaptic signaling, and transcriptional regulation, implicating key transcriptional regulators associated with both schizophrenia and neurodevelopmental disorders. The researchers hope that the insights gained from this research will pave the way for improved clinical outcomes for individuals affected by schizophrenia. They are now expanding their research to investigate other regions of the brain and the molecular impact of other psychiatric diseases such as bipolar disorder, as well as exploring how cell type-specific gene expression changes lead to functional and potentially druggable changes in the protein space.

Lead author Dr. W. Brad Ruzicka, director of the Laboratory for Epigenomics in Human Psychopathology at McLean Hospital, emphasizes the importance of advancing the understanding of schizophrenia pathophysiology at a greater level of detail. By unraveling the genetic and environmental underpinnings of this complex disease, researchers hope to provide better care for individuals with schizophrenia. The study’s authors are working towards tailoring future treatments to target specific genes and cell types, as well as specific individuals with schizophrenia, in order to improve clinical outcomes and provide more personalized care for those affected by this debilitating disorder.

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