Postmortem transcriptional profiling reveals widespread increase in inflammation in schizophrenia: a comparison of prefrontal cortex, striatum, and hippocampus among matched tetrads of controls with subjects diagnosed with schizophrenia, bipolar or major depressive disorder

Thomas A Lanz,Robin J Kleiman,Dmitri Volfson,Susan E Bove,David A Lewis,Stacey J Sukoff Rizzo,Larry C James,Mark J Sheehan,Veronica Reinhart

doi:10.1038/s41398-019-0492-8

Abstract

Psychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) arise from complex interactions between genetic and environmental factors. Common genetic variants associated with multiple psychiatric disorders suggest that shared genetic architecture could contribute to divergent clinical syndromes. To evaluate shared transcriptional alterations across connected brain regions, Affymetrix microarrays were used to profile postmortem dorsolateral prefrontal cortex (DLPFC), hippocampus, and associative striatum from 19 well-matched tetrads of subjects with SCZ, BD, MDD, or unaffected controls. SCZ subjects showed a substantial burden of differentially expressed genes across all examined brain regions with the greatest effects in hippocampus, whereas BD and MDD showed less robust alterations. Pathway analysis of transcriptional profiles compared across diagnoses demonstrated commonly enriched pathways between all three disorders in hippocampus, significant overlap between SCZ and BD in DLPFC, but no significant overlap of enriched pathways between disorders in striatum. SCZ samples showed increased expression of transcripts associated with inflammation across all brain regions examined, which was not evident in BD or MDD, or in rat brain following chronic dosing with antipsychotic drugs. Several markers of inflammation were confirmed by RT-PCR in hippocampus, including S100A8/9, IL-6, MAFF, APOLD1, IFITM3, and BAG3. A cytokine ELISA panel showed significant increases in IL-2 and IL-12p70 protein content in hippocampal tissue collected from same SCZ subjects when compared to matched control subjects. These data suggest an overlapping subset of dysregulated pathways across psychiatric disorders; however, a widespread increase in inflammation appears to be a specific feature of the SCZ brain and is not likely to be attributable to chronic antipsychotic drug treatment.

Highlights

Psychiatric disorders arise from complex interactions between genetic and environmental factors, which change developmental trajectories of circuits underpinning a continuum of neuro-functional domains[1]
The present study focused on three major psychiatric disorders with overlapping symptom domains: schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD)
Cryostat sections cut from Brodmann Area 46, associative subregion of dorsal striatum, and hippocampus were collected into empty tubes or tubes containing TRIzol (Life Technologies, Carlsbad, CA), from which RNA was extracted using a phenolchloroform extraction method

Summary

Introduction

Psychiatric disorders arise from complex interactions between genetic and environmental factors, which change developmental trajectories of circuits underpinning a continuum of neuro-functional domains[1]. One approach to identifying these molecular and biochemical differences is to examine molecular profiles of postmortem brains from subjects with clinically defined psychiatric disorders and unaffected comparison subjects. Despite limitations of studyspecific findings related to individual genes, multiple cellular pathways have been consistently represented by dysregulated genes identified across studies of schizophrenia, which fall into several broad categories including immune function, oxidative phosphorylation and mitochondrial function, synaptic transmission, and myelination/glial function. These trends have been further borne out by a recent ‘mega-analysis’ to reanalyze 19 brainbased gene expression studies[5]

Methods

Results

Conclusion