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

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.

Meta-Analysis of Transcriptomic Data of Dorsolateral Prefrontal Cortex and of Peripheral Blood Mononuclear Cells Identifies Altered Pathways in Schizophrenia

“…Finally, three datasets were included in the meta-analysis-GSE53987, GSE12649 and GSE21138-as they were all generated on the BA46 area. Briefly, the GSE53987 dataset included 19 samples from healthy people and 15 samples from SCZ patients [19]. The GSE12649 dataset included 34 healthy control samples and 35 samples from SCZ patients [20].…”

“…or saline for 21 days (n = 4 rats per group) [23]. The GSE66277 included whole-genome expression data from male Sprague-Dawley rats treated with either 0.25 mg/kg/day haloperidol, 5 mg/kg/day risperidone or vehicle (1% acetic acid in water) for 21 days (n = 5 rats per group) [19]. For both datasets, the Affymetrix Rat Genome 230 2.0 Array was used.…”

Abnormal features of human self-domestication in bipolar disorder

“…For this, we relied on available datasets of differentially expressed genes (DEGs) as found in the GEO repository (https://www.ncbi.nlm.nih.gov/gds). Specifically, we made use of recent data produced by Lanz and colleagues (2019) (GSE53987; supplemental table 5), who analyzed DEGs in postmortem samples of the prefrontal cortex (PFC), the hippocampus (HIP), and the striatum (STR) of people with BD. We considered only DEGs with expression p -values < 0.01 (see Supplemental file 3).…”

Altered Expression of a Unique Set of Genes Reveals Complex Etiology of Schizophrenia

“…The RNA was originally isolated from post-mortem brain tissue across three specific regions (hippocampus [ [STR]). For the original data, designated tissue samples were acquired from the curated collection of brain samples from the University of Pittsburgh which was permitted by the institute ethics committee (21,22). Equal numbers of male and female (except for odd number samples) diagnosed SCZ cases and controls of adult age were chosen for this purpose ( Table S1).…”

“…Fromer and colleagues (18) have identified over 100 of genetic loci harboring SCZ associated variants which together involve scores of genes, and altering the expression or knock down of some of such genes in animal or human stem cell models has shown to compromise neural functions effectively (18). Plausibly, the dysregulation of the neuronal genes, especially which are involved in maintaining basic cell architecture and machinery, may compromise the information processing in neurons in affected brain regions in SCZ (19,20).…”