Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes.

Alessandra Paparelli,Nori Takei,Keiko Iwata,Robin M Murray,Conrad Iyegbe,Tomoyasu Wakuda

doi:10.3389/fnmol.2017.00341

Abstract

Epidemiological studies suggest that obstetric complications, particularly those related to hypoxia during labor and delivery, are a risk factor for development of schizophrenia. The impact of perinatal asphyxia on postnatal life has been studied in a rodent model of global hypoxia, which is accompanied by cesarean section birth. This asphyxia model shows several behavioral, pharmacological, neurochemical, and neuroanatomical abnormalities in adulthood that have relevance to schizophrenia. Further, it is suggested that schizophrenia has a strong genetic component, and indeed novel candidate genes were recently identified by a genome-wide association study. Here, we examined alteration in the novel schizophrenia risk genes, CNNM2, CSMD1, and MMP16 in the brains of rats undergoing cesarean section with or without global hypoxia. The brain regions studied were the prefrontal cortex, striatum, and hippocampus, which are all relevant to schizophrenia. Risk gene expression was measured at three time periods: neonatal, adolescence, and adulthood. We also performed an in vitro analysis to determine involvement of these genes in CNS maturation during differentiation of human neuronal and glial cell lines. Cnnm2 expression was altered in the brains of asphyxia model rats. However, Csmd1 and Mmp16 showed altered expression by exposure to cesarean section only. These findings suggest that altered expression of these risk genes via asphyxia and cesarean section may be associated, albeit through distinct pathways, with the pathobiology of schizophrenia.

Highlights

Schizophrenia is a mental disorder with an often chronic course, presenting with various symptoms including delusions, hallucinations, and impaired cognition
Another line of investigation suggests a strong genetic component to schizophrenia. This is exemplified by a recent GenomeWide Association Study (GWAS) that identified a number of genetic elements that predispose to schizophrenia (Gershon et al, 2011; Schizophrenia Psychiatric Genome-Wide Association Study [GWAS] Consortium, 2011; Aberg et al, 2013; CrossDisorder Group of the Psychiatric Genomics Consortium, 2013; Ripke et al, 2013)
We determined if these novel schizophrenia risk genes show altered expression in asphyxia-induced rats. Among these five novel schizophrenia risk genes, we focused on Cnnm2, CUB and Sushi multiple domains 1 (Csmd1), and matrix metallopeptidase 16 (Mmp16) in this study

Summary

Introduction

Schizophrenia is a mental disorder with an often chronic course, presenting with various symptoms including delusions, hallucinations, and impaired cognition. Another line of investigation suggests a strong genetic component to schizophrenia This is exemplified by a recent GenomeWide Association Study (GWAS) that identified a number of genetic elements that predispose to schizophrenia (Gershon et al, 2011; Schizophrenia Psychiatric Genome-Wide Association Study [GWAS] Consortium, 2011; Aberg et al, 2013; CrossDisorder Group of the Psychiatric Genomics Consortium, 2013; Ripke et al, 2013). On top of these separate viewpoints (i.e., environmental risk vs genes), researchers highlight the likelihood of interplay between environmental risk and genes on predisposition to complex diseases such as schizophrenia (Ibi and Gonzalez-Maeso, 2015)

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Conclusion