Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia.
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.
Schmidt-Kastner
Rainald
R
Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands. rsk@np.unimaas.nl
van Os
Jim
J
W M Steinbusch
Harry
H
Schmitz
Christoph
C
D000818:Animals; D001921:Brain / Q000196:embryology / Q000503:physiopathology; D047109:Fetal Development / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D020925:Hypoxia-Ischemia, Brain / Q000196:embryology / Q000235:genetics / Q000503:physiopathology; D000091042:Reelin Protein; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics; D015854:Up-Regulation
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000091042:Reelin Protein; C000717127:RELN protein, human