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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3267-3276 |
| Number of pages | 10 |
| Journal | Molecular Neurobiology |
| Volume | 53 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jul 1 2016 |
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Keywords
- Behavior
- Blood flow
- Mice
- Prenatal hypoxia
- Reelin
- Schizophrenia
- Stress
- VEGF
ASJC Scopus subject areas
- Neurology
- Cellular and Molecular Neuroscience
Cite this
Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice. / Howell, Kristy R.; Pillai, Anilkumar.
In: Molecular Neurobiology, Vol. 53, No. 5, 01.07.2016, p. 3267-3276.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice
AU - Howell, Kristy R.
AU - Pillai, Anilkumar
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
KW - Behavior
KW - Blood flow
KW - Mice
KW - Prenatal hypoxia
KW - Reelin
KW - Schizophrenia
KW - Stress
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=84930800610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930800610&partnerID=8YFLogxK
U2 - 10.1007/s12035-015-9265-4
DO - 10.1007/s12035-015-9265-4
M3 - Article
C2 - 26059812
AN - SCOPUS:84930800610
VL - 53
SP - 3267
EP - 3276
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
IS - 5
ER -