Decoding schizophrenia through postmortem human brain transcriptomics

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Schizophrenia is a heritable neuropsychiatric disorder affecting ~1% of the population.
• Its pathophysiology remains unclear due to a lack of gross neuropathological changes.
• Transcriptomic profiling of postmortem brain tissue offers insights into molecular architecture.

Purpose of the Study:

• To synthesize findings from transcriptomics studies on schizophrenia.
• To elucidate the molecular underpinnings of schizophrenia pathophysiology.
• To identify cell types and gene expression patterns associated with schizophrenia.

Main Methods:

• Review of case-control bulk tissue transcriptomics studies.
• Analysis of single-nucleus transcriptomics data.
• Synthesis of findings from multiple large-scale consortia.

Main Results:

• Schizophrenia exhibits widespread, subtle gene expression changes in the prefrontal cortex, concentrated in excitatory neurons.
• Consistent downregulation of synaptic and metabolic genes observed.
• Secondary activation of glial populations noted.
• Transcriptional alterations are cell type-specific and heterogeneous, with upper-layer excitatory neurons being particularly vulnerable.

Conclusions:

• Transcriptional dysregulation is a core feature of schizophrenia pathophysiology.
• Single-cell resolution reveals cell type-specific and individual heterogeneity in molecular alterations.
• Future research should expand cohorts, brain regions, and employ advanced techniques like spatial transcriptomics.