Molecular signature of extracellular matrix pathology in schizophrenia

Abstract

Growing evidence points to a critical involvement of the extracellular matrix (ECM) in the pathophysiology of schizophrenia (SZ). Decreases of perineuronal nets (PNNs) and altered expression of chondroitin sulphate proteoglycans (CSPGs) in glial cells have been identified in several brain regions. GWAS data have identified several SZ vulnerability variants of genes encoding for ECM molecules. Given the potential relevance of ECM functions to the pathophysiology of this disorder, it is necessary to understand the extent of ECM changes across brain regions, their region-and sexspecificity and which ECM components contribute to these changes. We tested the hypothesis that the expression of genes encoding for ECM molecules may be broadly disrupted in SZ across several cortical and subcortical brain regions and include key ECM components as well as factors such as ECM posttranslational modifications and regulator factors. Gene expression profiling of 14 neocortical brain regions, caudate, putamen and hippocampus from control subjects (n = 14/region) and subjects with SZ (n = 16/region) was conducted using Affymetrix microarray analysis. Analysis across brain regions revealed widespread dysregulation of ECM gene expression in cortical and subcortical brain regions in SZ, impacting several ECM functional key components. SRGN, CD44, ADAMTS1, ADAM10, BCAN, NCAN and SEMA4G showed some of the most robust changes. Region-, sex-and age-specific gene expression patterns and correlation with cognitive scores were also detected. Taken together, these findings contribute to emerging evidence for large-scale ECM dysregulation in SZ and point to molecular pathways involved in PNN decreases, glial cell dysfunction and cognitive impairment in SZ.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Sleep and Memory Consolidation Dysfunction in Psychiatric Disorders: Evidence for the Involvement of Extracellular Matrix Molecules

“…Our group and others have reported PNN deficits in several brain regions in SZ (Pantazopoulos et al, 2010b(Pantazopoulos et al, , 2014(Pantazopoulos et al, , 2015Mauney et al, 2013;Enwright et al, 2016;Steullet et al, 2017). Furthermore, we recently reported broad alterations of ECM molecule gene expression in subjects with SZ associated with cognitive deficits, impacting CSPG core proteins, chondroitin sulfate synthesis pathways, and endogenous proteases across several cortical and subcortical brain regions (Pantazopoulos et al, 2020b). Recent evidence for altered diurnal molecular expression rhythms of subjects with SZ (Seney et al, 2019) suggests broad molecular circadian rhythm disturbances, which may impact several of these memory consolidation processes in which ECM molecules are involved.…”

Bioinformatics analysis of long non-coding RNA-associated competing endogenous RNA network in schizophrenia

“…More research is required to understand these conflicting findings. Also, contradictory results have been obtained from the study of CD44 84 – 86 and SPARC 87 dysregulation components of the brain extracellular matrix, in some brain regions. Another key gene in our study was SOX2 .…”

Brain extracellular matrix: An upcoming target in neurological and psychiatric disorders

“…The researchers report that this SNP correlates with reduced verbal memory, hippocampal overactivation during novelty encoding and reduced prefrontal grey matter density, pointing to an intermediate phenotype. Pantazopoulos et al (2020) focus on characteristic molecular ECM signatures in the brains of schizophrenic patients. They employed gene expression profiling of parceled cortical and subcortical areas to demonstrate complex patterns of dysregulation of ECM elements.…”

“…Pantazopoulos et al. (2020) focus on characteristic molecular ECM signatures in the brains of schizophrenic patients. They employed gene expression profiling of parceled cortical and subcortical areas to demonstrate complex patterns of dysregulation of ECM elements.…”