Activity-Dependent Changes in Gene Expression in Schizophrenia Human-Induced Pluripotent Stem Cell Neurons

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia is linked to candidate genes involved in neuronal activity-dependent pathways.
• Understanding activity-dependent gene expression changes is crucial for elucidating schizophrenia's pathogenesis.

Purpose of the Study:

• To investigate if neuronal activity-dependent gene expression is dysregulated in schizophrenia.
• To identify specific molecular pathways and gene networks affected in schizophrenia.

Main Methods:

• Utilized human induced pluripotent stem cell-derived neurons from individuals with schizophrenia and controls.
• Performed genome-wide transcriptome profiling after neuronal depolarization.
• Employed differential expression and gene coexpression analyses to identify disease-specific and activity-dependent changes.

Main Results:

• Identified significant differences in gene expression between schizophrenia-associated and control neurons.
• Observed an attenuated effect of activity-dependent gene expression changes in schizophrenia neurons compared to controls.
• Discovered gene coexpression modules associated with diagnosis and depolarization, with enrichment for schizophrenia risk variants.

Conclusions:

• Schizophrenia candidate genes are part of networks showing a blunted response to neuronal activity.
• These findings connect schizophrenia genes to specific neuronal functions, aiding in understanding mechanisms and developing therapies.