title: Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study.
abstract: Both genetic and environmental factors play important roles in the pathophysiology of schizophrenia. Although prenatal hypoxia is a potential environmental factor implicated in schizophrenia, very little is known about the consequences of combining models of genetic risk factor with prenatal hypoxia. Heterozygous reeler (haploinsufficient for reelin; HRM) and wild-type (WT) mice were exposed to prenatal hypoxia (9% oxygen for two hour) or normoxia at embryonic day 17 (E17). Behavioral (Prepulse inhibition, Y-maze and Open field) and functional (regional volume in frontal cortex and hippocampus as well as hippocampal blood flow) tests were performed at 3 months of age. The levels of hypoxia and stress-related molecules such as hypoxia-inducible factor-1 α (HIF-1α), vascular endothelial factor (VEGF), VEGF receptor-2 (VEGFR2/Flk1) and glucocorticoid receptor (GR) were examined in frontal cortex and hippocampus at E18, 1 month and 3 months of age. In addition, serum VEGF and corticosterone levels were also examined. Prenatal hypoxia induced anxiety-like behavior in both HRM and WT mice. A significant reduction in hippocampal blood flow, but no change in brain regional volume was observed following prenatal hypoxia. Significant age and region-dependent changes in HIF-1α, VEGF, Flk1 and GR were found following prenatal hypoxia. Serum VEGF and corticosterone levels were found decreased following prenatal hypoxia. None of the above prenatal hypoxia-induced changes were either diminished or exacerbated due to reelin deficiency. These results argue against any gene-environment interaction between hypoxia and reelin deficiency.
authors.affiliation: Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, 997 St. Sebastian Way, Augusta, GA 30912, USA.
authors.forename: Kristy R
authors.initials: KR
authors.lastname: Howell
authors.affiliation: Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, 997 St. Sebastian Way, Augusta, GA 30912, USA. Electronic address: apillai@gru.edu.
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Pillai
mesh_terms: D000161:Acoustic Stimulation; D000704:Analysis of Variance; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000473:pathology; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D060005:Genotyping Techniques; D006624:Hippocampus / Q000473:pathology; D000860:Hypoxia / Q000150:complications* / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007266:Inhibition, Psychological; D008279:Magnetic Resonance Imaging; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics / Q000503:physiopathology*; D011571:Psychoacoustics; D000091042:Reelin Protein; D012039:Regional Blood Flow; D012559:Schizophrenia / Q000097:blood / Q000209:etiology* / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D003345:Corticosterone
keywords: Mice; Prenatal hypoxia; Reelin; Schizophrenia; VEGF