Schizophrenia’s diverse nature complicates treatment development, but a recent studyt unveils novel insights into the intricate molecular mechanisms of the disorder, as per McLean Hospital researchers, puiblished in the journal Science ().

“We discovered which cell types express genes associated with schizophrenia risk differently, which biological functions are impacted within those cells, and which transcription factors are important for these changes,” explained lead and co-corresponding author, W. Brad Ruzicka MD, PhD, director of the Laboratory for Epigenomics in Human Psychopathology at McLean Hospital.

“This understanding will allow future treatments to be tailored to specific genes and cell types, as well as individuals with schizophrenia.”

Schizophrenia affects approximately 24 million people, or 1 in 300 people, worldwide, according to the World Health Organization.

For the new study, a multi-center team of researchers conducted a comprehensive single-cell analysis of transcriptomic changes in the human prefrontal cortex, examining postmortem brain tissue from 140 individuals across two independent cohorts. Their analyses included more than 468,000 cells.

They uncovered unprecedented insights into the cellular basis of schizophrenia, linking genetic risk factors to specific neuronal populations.

Specifically, the researchers found that excitatory neurons emerged as the most affected cell group, with transcriptional changes implicating neurodevelopment and synapse-related pathways.

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Additionally, they found that known genetic risk factors for schizophrenia converge on alterations in specific neuronal populations, highlighting the interplay between rare and common genomic variants.

Through transcriptomic analysis, two distinct subpopulations of individuals with schizophrenia were identified, marked by the expression of specific excitatory and inhibitory neuronal cell states.

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Genetic Clues in the Schizophrenia’s Mysteries

The new 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 study’s authors anticipate that insights gleaned from this research could pave the way for targeted interventions and personalized treatments for schizophrenia, potentially improving clinical outcomes for individuals affected by this debilitating and often disabling disorder.

The research team is now working to expand on these findings by investigating other regions of the brain and the molecular impact of other psychiatric diseases such as bipolar disorder.

They are also pursuing another dimension of complexity in this system by investigating isoform expression of implicated genes and how these cell type-specific gene expression changes lead to functional and potentially druggable changes in the protein space.

“This work advances understanding of schizophrenia pathophysiology at greater detail across both the complex landscape of cells within the brain, and the diverse experiences of people with this disease,” said Ruzicka, who is also associate medical director of Harvard Brain Tissue Resource Center at McLean, and an assistant professor of Psychiatry at Harvard Medical School.

“Our increased mechanistic understanding of schizophrenia provides avenues for future research to unravel the genetic and environmental underpinnings of this complex disease so we can provide our patients better care.”

Reference:

1. Single-cell multi-cohort dissection of the schizophrenia transcriptome
   – (https://www.science.org/doi/10.1126/science.adg5136)

Source-Eurekalert