Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

Abstract

The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome-wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age-related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease-associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease-relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway-specific therapeutic opportunities to treat negative or positive symptoms of the disease.

Gene expression‐based drug repurposing to target aging

“…We analysed data from seven, published, microarray‐based studies of age‐related changes in RNA expression (Barnes et al, 2011; Berchtold et al, 2008; Colantuoni et al, 2011; Kang et al, 2011; Lu et al, 2004; Maycox et al, 2009; Somel et al, 2010, 2011 ). The data came from 22 different brain regions, and the ages of the donors ranged from 20 to 106 years (Figure 1a and Supporting Information Figure S1a).…”

Transcriptomic evidence for immaturity of the prefrontal cortex in patients with schizophrenia

“…Fifteen publicly available microarray data sets were used in this study (Table  1): four data sets on the developing human cortices (GSE13564 [31], GSE25219 [33], GSE11512 [34], GSE37721 [94]), five on the schizophrenic cortices (GSE21138 [32], GSE17612 [36], GSE12649 [35], GSE53987, GSE21935 [95]), two on developing mouse cortex or cells (GSE17806 [37], GSE9566 [38], GSE4675 [96]), one on the medial frontal cortex (MFC) of the schizophrenia mouse model Shn-2 KO mice (GSE42775 [11]), and two on the frontal cortices of rodents treated with antipsychotic drug (GSE45229 [97], GSE2547 [98]). Patient demographics have been previously described in detail [32,35,36,95].…”

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

“…In particular, at BA 22, the vast majority of abnormally expressed genes referred to key autophagy genes (i.e., BECN1 , ULK2 , ATG3 ), which were significantly down-regulated compared with controls [249]. A few months later, another transcriptomic study reported a BA 22-specific down-regulation in several autophagy-related genes, thus strengthening the link between impaired autophagy and schizophrenia positive symptoms [252]. Furthermore, the transcriptional analysis performed on the very same post-mortem samples demonstrated no substantial changes in the mRNA levels of the above-mentioned autophagy-related genes within the anterior prefrontal cortex (BA 10), which is mainly involved in schizophrenic negative symptoms and cognitive dysfunction, thus reinforcing the involvement of an impaired autophagy in mediating positive symptoms.…”