Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res

Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands.
Schizophrenia Research (Impact Factor: 3.92). 07/2006; 84(2-3):253-71. DOI: 10.1016/j.schres.2006.02.022
Source: PubMed


Neurodevelopmental changes may underlie the brain dysfunction seen in schizophrenia. While advances have been made in our understanding of the genetics of schizophrenia, little is known about how non-genetic factors interact with genes for schizophrenia. The present analysis of genes potentially associated with schizophrenia is based on the observation that hypoxia prevails in the embryonic and fetal brain, and that interactions between neuronal genes, molecular regulators of hypoxia, such as hypoxia-inducible factor 1 (HIF-1), and intrinsic hypoxia occur in the developing brain and may create the conditions for complex changes in neurodevelopment. Consequently, we searched the literature for currently hypothesized candidate genes for susceptibility to schizophrenia that may be subject to ischemia-hypoxia regulation and/or associated with vascular expression. Genes were considered when at least two independent reports of a significant association with schizophrenia had appeared in the literature. The analysis showed that more than 50% of these genes, particularly AKT1, BDNF, CAPON, CCKAR, CHRNA7, CNR1, COMT, DNTBP1, GAD1, GRM3, IL10, MLC1, NOTCH4, NRG1, NR4A2/NURR1, PRODH, RELN, RGS4, RTN4/NOGO and TNF, are subject to regulation by hypoxia and/or are expressed in the vasculature. Future studies of genes proposed as candidates for susceptibility to schizophrenia should include their possible regulation by physiological or pathological hypoxia during development as well as their potential role in cerebral vascular function.

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    • "Overall, our enrichment findings implicating cGMP (triggering vasodilation ) and cardiomyopathy are consistent with mounting evidence implicating vasodilation and vasculature in SCZ. Many of the replicated candidate genes for SCZ are expressed in vasculature (Schmidt-Kastner et al., 2006, 2012). Evidence also suggests that people with SCZ have greater vulnerability to cardiovascular disease (Hennekens et al., 2005) and that genetic pleiotropy exists between SCZ and risk for cardiovascular disease (Andreassen et al., 2013). "
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    ABSTRACT: Empirically derived phenotypic measurements have the potential to enhance gene-finding efforts in schizophrenia. Previous research based on factor analyses of symptoms has typically included schizoaffective cases. Deriving factor loadings from analysis of only narrowly defined schizophrenia cases could yield more sensitive factor scores for gene pathway and gene ontology analyses. Using an Irish family sample, this study 1) factor analyzed clinician-rated Operational Criteria Checklist items in cases with schizophrenia only, 2) scored the full sample based on these factor loadings, and 3) implemented genome-wide association, gene-based, and gene-pathway analysis of these SCZ-based symptom factors (final N=507). Three factors emerged from the analysis of the schizophrenia cases: a manic, a depressive, and a positive symptom factor. In gene-based analyses of these factors, multiple genes had q<0.01. Of particular interest are findings for PTPRG and WBP1L, both of which were previously implicated by the Psychiatric Genomics Consortium study of SCZ; results from this study suggest that variants in these genes might also act as modifiers of SCZ symptoms. Gene pathway analyses of the first factor indicated over-representation of glutamatergic transmission, GABA-A receptor, and cyclic GMP pathways. Results suggest that these pathways may have differential influence on affective symptom presentation in schizophrenia. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Mar 2015 · Schizophrenia Research
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    • "Both the catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) genes are also regulated by hypoxia (Schmidt- Kastner et al., 2006), and are associated with the dopamine system in the brain; COMT is an enzyme involved in the degradation of dopamine and BDNF is one of the trophic factors involved in the development of dopaminergic neurons (Baquet et al., 2005). V-akt murine thymoma viral oncogene homolog 1 (AKT1), a component of the downstream signaling pathways of both NRG1/ErbB4 and BDNF, is also one of the schizophrenia candidate genes that are regulated by hypoxia (Emamian et al., 2004; Schmidt-Kastner et al., 2006; Thiselton et al., 2008). Moreover, AKT1 mediates dopaminergic neurotransmission (Beaulieu et al., 2005). "
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    ABSTRACT: Epidemiological studies suggest that perinatal complications, particularly hypoxia-related ones, increase the risk of schizophrenia. Recent genetic studies of the disorder have identified several putative susceptibility genes, some of which are known to be regulated by hypoxia. It can be postulated therefore that birth complications that cause hypoxia in the fetal brain may be associated with a dysregulation in the expression of some of the schizophrenia candidate genes. To test this, we used an animal model of perinatal asphyxia, in which rat pups were exposed to 15min of intrauterine anoxia during Caesarean section birth, and examined the expression of mRNA of five of the putative susceptibility genes (NRG1, ErbB4, AKT1, COMT and BDNF) by real-time quantitative PCR in the medial prefrontal cortex (mPFC) and the hippocampus at 6 and 12weeks after birth. The expression of NRG1 mRNA was significantly decreased in the mPFC, but not in the hippocampus, at 6 and 12weeks after birth. In addition, a significant increase in COMT mRNA expression was observed in the mPFC at 12weeks. The alteration in mRNA levels of NRG1 and COMT was not associated with a change in their protein levels. These results suggest that perinatal asphyxia may lead to disturbances in the PFC, which in turn may exert a long-lasting influence on the expression of specific genes, such as NRG1 and COMT. Our results also suggest that translational interruption may occur in this model of perinatal asphyxia.
    Full-text · Article · Sep 2014 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "Obstetrical complications, especially fetal hypoxia, are associated with a 1.5–3 times increased risk for schizophrenia [3] [4] [5]. More than 50% of candidate genes for susceptibility to schizophrenia are subject to regulation by hypoxia and/or are expressed in the vasculature [6]. These results suggest strong linkage between neurodevelopmental hypoxia and schizophrenia. "
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    ABSTRACT: Several prospective studies indicated perinatal hypoxia as risk factor for psychiatric disorders like schizophrenia. It is thought that hypoxia prior to or during birth may contribute to alterations leading to the protracted clinical manifestation during young adulthood. However, only a small fraction of children with a history of perinatal hypoxia develop later psychotic symptoms, therefore it is not known if hypoxia alone is sufficient to trigger long-term behavioral changes. Here we exposed C57BL/6 mice from Postnatal Day 3-7 (P3-P7) to two established paradigms of chronic mild hypoxia (10% ambient O2), intermittent and continuous. Subsequently, mice were analysed during young adult stages using several basic behavioural tests. Previous studies demonstrated severe, but only transient, cortical damage in these paradigms; it is not clear, if these reversible morphological changes are accompanied by long-term behavioural effects. We found that neither intermittent nor continuous perinatal hypoxia induced long-term behavioral alterations. This may be due to the high regenerative capacity of the perinatal brain. Other possibilities include a potential resistance to perinatal hypoxia of the mouse strain used here or a level of hypoxia that was insufficient to trigger significant behavioral changes. Therefore, our data do not exclude a role of perinatal hypoxia as risk factor for psychiatric disorders. They rather suggest that either other, more severe hypoxic conditions like anoxia, or the presence of additional factors (as genetic risk factors) are necessary for generating long-term behavioral abnormalities.
    Full-text · Article · Jun 2014 · Neuroscience Letters
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