title: Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice.
abstract: Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizophrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies, we examined the long-term effects of PHX in heterozygous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6 months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor-1α (HIF-1α) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorticoid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene-environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specificity of the gene of interest.
authors.affiliation: Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA, USA.|Department of Psychiatry, University of Colorado Denver, School of Medicine, Aurora, CO, USA.
authors.forename: Kristy R
authors.initials: KR
authors.lastname: Howell
authors.affiliation: Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA, USA. apillai@gru.edu.
authors.forename: Anilkumar
authors.initials: A
authors.lastname: Pillai
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003345:Corticosterone / Q000097:blood; D006579:Heterozygote; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D000860:Hypoxia / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D018782:Maze Learning; D008818:Mice, Neurologic Mutants; D010641:Phenotype; D065808:Prepulse Inhibition / Q000502:physiology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D000091042:Reelin Protein; D013216:Reflex, Startle / Q000502:physiology; D012559:Schizophrenia / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D013647:Task Performance and Analysis; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D011965:Receptors, Glucocorticoid; D000091042:Reelin Protein; D042461:Vascular Endothelial Growth Factor A; C000717128:Reln protein, mouse; D003345:Corticosterone
keywords: Behavior; Blood flow; Mice; Prenatal hypoxia; Reelin; Schizophrenia; Stress; VEGF