Molecular Neurobiology

, Volume 53, Issue 5, pp 3267–3276 | Cite as

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



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.


Reelin Prenatal hypoxia Mice Stress Schizophrenia VEGF Blood flow Behavior 


  1. 1.
    Lillrank SM, Lipska BK, Weinberger DR (1995) Neurodevelopmental animal models of schizophrenia. Clin Neurosci 3(2):98–104PubMedGoogle Scholar
  2. 2.
    Bayer TA, Falkai P, Maier W (1999) Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the “two hit hypothesis”. J Psychiatr Res 33(6):543–548CrossRefPubMedGoogle Scholar
  3. 3.
    Marenco S, Weinberger DR (2000) The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave. Dev Psychopathol 12:501–527CrossRefPubMedGoogle Scholar
  4. 4.
    Fatemi SH, Folsom TD (2009) The neurodevelopmental hypothesis of schizophrenia, revisited. Schizophr Bull 35(3):528–548CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Rapoport JL, Addington AM, Frangou S, Psych MR (2005) The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry 10(5):434–449CrossRefPubMedGoogle Scholar
  6. 6.
    Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10(1):40–68CrossRefPubMedGoogle Scholar
  7. 7.
    Demjaha A, MacCabe JH, Murray RM (2011) How genes and environmental factors determine the different neurodevelopmental trajectories of schizophrenia and bipolar disorder. Schizophr BullGoogle Scholar
  8. 8.
    Clarke MK, Harley M, Cannon M (2006) The role of obstetric events in schizophrenia. Schizophr Bull 32(1):3–8CrossRefPubMedGoogle Scholar
  9. 9.
    Nicodemus KK, Marenco S, Batten AJ, Vakkalanka R, Egan MF, Straub RE, Weinberger DR (2008) Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk. Mol Psychiatry 13(9):873–877CrossRefPubMedGoogle Scholar
  10. 10.
    Boksa P (2004) Animal models of obstetric complications in relation to schizophrenia. Brain Res Rev 45:1–17CrossRefPubMedGoogle Scholar
  11. 11.
    Van Erp TG, Saleh PA, Rosso IM, Huttunen M, Lönnqvist J, Pirkola T, Salonen O, Valanne L et al (2002) Contributions of genetic risk and fetal hypoxia to hippocampal volume in patients with schizophrenia or schizoaffective disorder, their unaffected siblings, and healthy unrelated volunteers. Am J Psychiatry 159:1514–1520CrossRefPubMedGoogle Scholar
  12. 12.
    Schmidt-Kastner R, van Os J, Steinbusch HWM, Schmitz C (2006) Gene regulation by hypoxia and the neurodevelopmental origin of schizophrenia. Schizophr Res 84(2–3):253–271CrossRefPubMedGoogle Scholar
  13. 13.
    Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev 56(4):549–580CrossRefPubMedGoogle Scholar
  14. 14.
    Storkebaum E, Carmeliet P (2004) VEGF: a critical player in neurodegeneration. J Clin Invest 113(1):14–18CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16(9):4604–4613CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Hanson DR, Gottesman II (2005) Theories of schizophrenia: a genetic-inflammatory-vascular synthesis. BMC Med Genet 6:7CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fulzele S, Pillai A (2009) Decreased VEGF mRNA expression in the dorsolateral prefrontal cortex of schizophrenia subjects. Schizophr Res 115(2–3):372–373CrossRefPubMedGoogle Scholar
  18. 18.
    Mayoral SR, Omar G, Penn AA (2009) Sex differences in a hypoxia model of preterm brain damage. Pediatr Res 66(3):248–253CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Asami T, Bouix S, Whitford TJ, Shenton ME, Salisbury DF, McCarley RW (2012) Longitudinal loss of gray matter volume in patients with first-episode schizophrenia: DARTEL automated analysis and ROI validation. Neuroimage 59(2):986–996CrossRefPubMedGoogle Scholar
  20. 20.
    Parlapani E, Schmitt A, Erdmann A, Bernstein HG, Breunig B, Gruber O, Petroianu G, von Wilmsdorff M et al (2009) Association between myelin basic protein expression and left entorhinal cortex pre-alpha cell layer disorganization in schizophrenia. Brain Res 1301:126–134CrossRefPubMedGoogle Scholar
  21. 21.
    Flynn SW, Lang DJ, Mackay AL, Goghari V, Vavasour IM, Whittall KP, Smith GN, Arango V et al (2003) Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins. Mol Psychiatry 8(9):811–820CrossRefPubMedGoogle Scholar
  22. 22.
    Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR et al (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc Natl Acad Sci U S A 95(26):15718–15723CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Fatemi SH, Earle JA, McMenomy T (2000) Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. Mol Psychiatry 5(6):654–663, 571 CrossRefPubMedGoogle Scholar
  24. 24.
    Jossin Y (2004) Neuronal migration and the role of reelin during early development of the cerebral cortex. Mol Neurobiol 30(3):225–251CrossRefPubMedGoogle Scholar
  25. 25.
    Laviola G, Ognibene E, Romano E, Adriani W, Keller F (2009) Gene-environment interaction during early development in the heterozygous reeler mouse: clues for modelling of major neurobehavioral syndromes. Neurosci Biobehav Rev 33(4):560–572CrossRefPubMedGoogle Scholar
  26. 26.
    Nullmeier S, Panther P, Dobrowolny H, Frotscher M, Zhao S, Schwegler H, Wolf R (2011) Region-specific alteration of GABAergic markers in the brain of heterozygous reeler mice. Eur J Neurosci 33(4):689–698CrossRefPubMedGoogle Scholar
  27. 27.
    Golan MH, Mane R, Molczadzki G, Zuckerman M, Kaplan-Louson V, Huleihel M, Perez-Polo JR (2009) Impaired migration signaling in the hippocampus following prenatal hypoxia. Neuropharmacology 57(5–6):511–522CrossRefPubMedGoogle Scholar
  28. 28.
    Costa E, Davis J, Pesold C, Tueting P, Guidotti A (2002) The heterozygote reeler mouse as a model for the development of a new generation of antipsychotics. Curr Opin Pharmacol 2(1):56–62CrossRefPubMedGoogle Scholar
  29. 29.
    Pillai A, Mahadik SP (2008) Increased truncated TrkB receptor expression and decreased BDNF/TrkB signaling in the frontal cortex of reeler mouse model of schizophrenia. Schizophr Res 100(1–3):325–333CrossRefPubMedGoogle Scholar
  30. 30.
    Howell KR, Pillai A (2014) Effects of prenatal hypoxia on schizophrenia-related phenotypes in heterozygous reeler mice: a gene × environment interaction study. Eur Neuropsychopharmacol 24(8):1324–1336CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Terry AV Jr, Parikh V, Gearhart DA, Pillai A, Hohnadel E, Warner S, Nasrallah HA, Mahadik SP (2006) Time-dependent effects of haloperidol and ziprasidone on nerve growth factor, cholinergic neurons, and spatial learning in rats. J Pharmacol Exp Ther 318:709–724CrossRefPubMedGoogle Scholar
  32. 32.
    Callahan PM, Terry AV Jr, Tehim A (2014) Effects of the nicotinic α7 receptor partial agonist GTS-21 on NMDA-glutamatergic receptor related deficits in sensorimotor gating and recognition memory in rats. Psychopharmacology (Berlin) 231(18):3695–3706CrossRefGoogle Scholar
  33. 33.
    Schulz KM, Pearson JN, Neeley EW, Berger R, Leonard S, Adams CE, Stevens KE (2011) Maternal stress during pregnancy causes sex-specific alterations in offspring memory performance, social interactions, indices of anxiety, and body mass. Physiol Behav 104(2):340–347CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Chung S, Son GH, Park SH, Park E, Lee KH, Geum D, Kim K (2005) Differential adaptive responses to chronic stress of maternally stressed male mice offspring. Endocrinology 146(7):3202–3210CrossRefPubMedGoogle Scholar
  35. 35.
    Tazumi T, Hori E, Uwano T, Umeno K, Tanebe K, Tabuchi E, Ono T, Nishijo H (2005) Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring. Behav Brain Res 162(1):153–160CrossRefPubMedGoogle Scholar
  36. 36.
    Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak RS (1992) Patterns of cerebral blood flow in schizophrenia. Br J Psychiatry 160:179–186CrossRefPubMedGoogle Scholar
  37. 37.
    Sahin S, Yüksel C, Güler J, Karadayı G, Akturan E, Göde E, Ozhan AA, Uçok A (2013) The history of childhood trauma among individuals with ultra high risk for psychosis is as common as among patients with first-episode schizophrenia. Early Interv Psychiatry 7:414–420CrossRefPubMedGoogle Scholar
  38. 38.
    Larsson S, Andreassen OA, Aas M, Røssberg JI, Mork E, Steen NE, Barrett EA, Lagerberg TV et al (2013) High prevalence of childhood trauma in patients with schizophrenia spectrum and affective disorder. Compr Psychiatry 54(2):123–127CrossRefPubMedGoogle Scholar
  39. 39.
    Lysaker PH, Meyer PS, Evans JD, Clements CA, Marks KA (2001) Childhood sexual trauma and psychosocial functioning in adults with schizophrenia. Psychiatr Serv 52(11):1485–1488CrossRefPubMedGoogle Scholar
  40. 40.
    Lima-Ojeda JM, Vogt MA, Richter SH, Dormann C, Schneider M, Gass P, Inta D (2014) Lack of protracted behavioral abnormalities following intermittent or continuous chronic mild hypoxia in perinatal C57BL/6 mice. Neurosci Lett 577:77–82CrossRefPubMedGoogle Scholar
  41. 41.
    Levy AP, Levy NS, Wegner S, Goldberg MA (1995) Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270(22):13333–13340CrossRefPubMedGoogle Scholar
  42. 42.
    Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A, Girnun G, Cooper M, Laznik D et al (2008) HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451(7181):1008–1012CrossRefPubMedGoogle Scholar
  43. 43.
    Howell KR, Hoda MN, Pillai A (2013) VEGF activates NR2B phosphorylation through Dab1 pathway. Neurosci Lett 552:30–34CrossRefPubMedGoogle Scholar
  44. 44.
    Pruessner M, Béchard-Evans L, Boekestyn L, Iyer SN, Pruessner JC, Malla AK (2013) Attenuated cortisol response to acute psychosocial stress in individuals at ultra-high risk for psychosis. Schizophr Res 146(1–3):79–86CrossRefPubMedGoogle Scholar
  45. 45.
    David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D et al (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62:479–493CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kutiyanawalla A, Promsote W, Terry A, Pillai A (2012) Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice. Int J Neuropsychopharmacol 15(8):1073–1086CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Psychiatry and Health BehaviorGeorgia Regents UniversityAugustaUSA
  2. 2.Department of PsychiatryUniversity of Colorado Denver, School of MedicineAuroraUSA

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