Largest RNA-Seq study of individuals with schizophrenia to date

Upregulation of the immune response may be involved in the pathogenesis of schizophrenia with changes occurring in both peripheral blood and brain tissue. To date, microarray technology has provided a limited view of specific inflammatory transcripts in brain perhaps due to sensitivity issues. Now, a team led by researchers at Neuroscience Research Australia has used SOLiD Next Generation Sequencing to quantify neuroimmune mRNA expression levels in the dorsolateral prefrontal cortex of 20 individuals with schizophrenia and their matched controls.

The current study is among the first to use NGS to examine the transcriptome of DLPFC from 20 individuals with schizophrenia and 20 matched controls, providing the most sensitive examination of gene expression changes in schizophrenia available to date. In addition, the RNA-Seq results were confirmed by quantitative PCR (qPCR) in an expanded cohort (n=74) in which microglial density was also measured through immunohistochemistry, cell counting, and western blotting.

The research team detected 798 differentially regulated transcripts present in people with schizophrenia compared with controls. Ingenuity pathway analysis identified the inflammatory response as a key change. They confirmed the changes (by QPCR) in candidate cytokines and immune modulators, including interleukin (IL)-6, IL-8, IL-1β and SERPINA3. The density of major histocompatibility complex-II-positive cells morphologically resembling microglia was significantly increased in schizophrenia and correlated with IL-1β expression. A group of individuals, most of whom had schizophrenia, were found to have increased inflammatory mRNA expression.

The proposed neuro-inflammatory pathwayThis study has demonstrated changes in an inflammatory response pathway that are present in ~40% of people diagnosed with schizophrenia. This suggests that therapies aimed at immune system attenuation in schizophrenia may be of direct benefit in the brain.

  • Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T, Cairns M, Weickert CS. (2012) Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry [Epub ahead of print]. [abstract]