Perinatal Asphyxia in Rat Alters Expression of Novel Schizophrenia Risk Genes

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.

Structural Insights into the Intracellular Region of the Human Magnesium Transport Mediator CNNM4

“…For example, mutations in CNNM2 or CNNM4 cause recessively inherited dominant hypomagnesemia and renal Mg 2+ wasting [2] or Jalili Syndrome, respectively [17][18][19][20][21][22][23]. Other disorders related to their altered activity include infertility [24,25], impaired brain development [26] along with neuropsychiatric disorders [27][28][29][30], and abnormal blood pressure levels [31]. On the other hand, CNNM3 and CNNM4 are involved in cancer progression [15,32] by associating with the highly oncogenic phosphatases of the regenerating liver (PRLs) and by promoting intracellular Mg 2+ accumulation that favors tumor growth and metastasis [6,[32][33][34].…”

Selective reduction in the expression of type‐1 metabotropic glutamate receptors in the hippocampus of adult rats born by caesarean section

“…For example, changes in two schizophrenia‐related genes, Csmd1 and Mmp16 that encode for CUB and Sushi multiple domains 1 and metallopeptodase 16, respectively, were recently found in the hippocampus and striatum of rats born by caesarean section (Paparelli et al., 2017) and loss‐of‐function mutations of the Grm1 gene encoding for the mGlu1 receptor have been associated with schizophrenia (Cho et al., 2014; Garcia‐Barrantes et al., 2015). Whether changes in these genes are interrelated is an interesting question that warrants further investigations.…”

Analysis of GWAS-Derived Schizophrenia Genes for Links to Ischemia-Hypoxia Response of the Brain

“…Expression studies in animal models or cell culture of human neurons may provide new insight. In vivo neonatal models of ischemia-hypoxia have demonstrated regulation of some schizophrenia-related genes (49), but this approach does not capture variation associated with risk of schizophrenia. Studies on developing neurons derived from human iPSCs and exposed to variations in oxygen conditions may shed further light on functional effects of SNPs identified in GWAS for schizophrenia.…”