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Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice

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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.

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Acknowledgments

The authors would like to send a special acknowledgement to the Small Animal Behavior Core Facility of Georgia Regents University for training of the authors and the use of the equipment for the behavioral analysis. The imaging and blood flow analysis were performed by the Core Imaging Facility for Small Animals at Georgia Regents University.

Compliance with Ethical Standards

The study was partially funded by the National Institute of Health (MH083215 to AP).The study described here was reviewed and approved by the Georgia Regents University Institutional Committee on Animal Use for Research. The experiments were performed in compliance with institutional animal welfare guidelines.

Conflict of Interest

The authors declare that they have no conflict of interest.

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  1. Kristy R. Howell

    Present address: Department of Psychiatry, University of Colorado Denver, School of Medicine, Aurora, CO, USA

Authors and Affiliations

  1. Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA, USA

    Kristy R. Howell & Anilkumar Pillai

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Correspondence to Anilkumar Pillai.

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Howell, K.R., Pillai, A. Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice. Mol Neurobiol 53, 3267–3276 (2016). https://doi.org/10.1007/s12035-015-9265-4

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  • DOI: https://doi.org/10.1007/s12035-015-9265-4

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