Skip to main content
SpringerLink
Log in

Perinatal Oxygen Restriction Does Not Result in Reduced Rat Frontal Cortex Synaptophysin Protein Levels at Adulthood as Opposed to Postmortem Findings in Schizophrenia

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Synaptophysin, a synaptic vesicle protein and a marker for synaptic density has been found to be reduced in postmortem prefrontal cortex of schizophrenia patients, consistent with evidence for synaptic deficits in schizophrenia. The contribution of both genetic and environmental factors to the etiology of schizophrenia is well established, and obstetric complications have been suggested as a non-genetic risk factor of schizophrenia. As there is only scarce evidence for a genetic linkage between synaptophysin’s chromosomal locus (Xp11.22) and schizophrenia, we hypothesized that early neonatal exposure of rat pups to oxygen restriction would result in reduced frontal cortex synaptophysin protein levels at adulthood. We studied the effects of anoxia or hypoxia on 7-day-old rats frontal cortex synaptophysin protein levels assessed by Western blotting 4 and 7 weeks following the exposure. In hypoxia- or anoxia-exposed rats, synaptophysin protein levels were elevated both 4 and 7 weeks after the exposure. Two-way ANOVA followed by post hoc LSD analysis showed that the effect was predominantly at 4 weeks after exposure and that only anoxia-exposed rats differed significantly from control rats (p = 0.019). These results are in contrast to postmortem findings in schizophrenia and suggest that reduced synaptophysin protein levels in schizophrenia patients’ postmortem brain do not result from perinatal oxygen deprivation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Abdel-Aleem, S., St Louis, J. D., Hughes, G. C., & Lowe, J. E. (1999). Metabolic changes in the normal and hypoxic neonatal myocardium. Annals of the New York Academy of Sciences, 874, 254–261. doi:10.1111/j.1749-6632.1999.tb09240.x.

    Article  PubMed  CAS  Google Scholar 

  • Barr, A. M., Young, C. E., Phillips, A. G., & Honer, W. G. (2006). Selective effects of typical antipsychotic drugs on SNAP-25 and synaptophysin in the hippocampal trisynaptic pathway. The International Journal of Neuropsychopharmacology, 9, 457–463.

    Article  PubMed  CAS  Google Scholar 

  • Boksa, P. (2004). Animal models of obstetric complications in relation to schizophrenia. Brain Research. Brain Research Reviews, 45, 1–17. doi:10.1016/j.brainresrev.2004.01.001.

    Article  PubMed  Google Scholar 

  • Boksa, P., & El-Khodor, B. F. (2003). Birth insult interacts with stress at adulthood to alter dopaminergic function in animal models: Possible implications for schizophrenia and other disorders. Neuroscience and Biobehavioral Reviews, 27, 91–101. doi:10.1016/S0149-7634(03)00012-5.

    Article  PubMed  CAS  Google Scholar 

  • Brake, W. G., Boksa, P., & Gratton, A. (1997). Effects of perinatal anoxia on the acute locomotor response to repeated amphetamine administration in adult rats. Psychopharmacology, 133, 389–395. doi:10.1007/s002130050419.

    Article  PubMed  CAS  Google Scholar 

  • Browning, M. D., Dudek, E. M., Rapier, J. L., Leonard, S., & Freedman, R. (1993). Significant reductions in synapsin but not synaptophysin specific activity in the brains of some schizophrenics. Biological Psychiatry, 34, 529–535. doi:10.1016/0006-3223(93)90195-J.

    Article  PubMed  CAS  Google Scholar 

  • Cannon, M., Jones, P. B., & Murray, R. M. (2002). Obstetric complications and schizophrenia: Historical and meta-analytic review. The American Journal of Psychiatry, 159, 1080–1092. doi:10.1176/appi.ajp.159.7.1080.

    Article  PubMed  Google Scholar 

  • Carmeliet, P., Dor, Y., Herbert, J. M., Fukumura, D., Brusselmans, K., Dewerchin, M., et al. (1998). Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature, 394, 485–490. doi:10.1038/28867.

    Article  PubMed  CAS  Google Scholar 

  • Decker, M. J., Hue, G. E., Caudle, W. M., Miller, G. W., Keating, G. L., & Rye, D. B. (2003). Episodic neonatal hypoxia evokes executive dysfunction and regionally specific alterations in markers of dopamine signaling. Neuroscience, 117, 417–425. doi:10.1016/S0306-4522(02)00805-9.

    Article  PubMed  CAS  Google Scholar 

  • Decker, M. J., & Rye, D. B. (2002). Neonatal intermittent hypoxia impairs dopamine signaling and executive functioning. Sleep and Breathing, 6, 205–210. doi:10.1055/s-2002-36531.

    Article  PubMed  Google Scholar 

  • Eastwood, S. L. (2004). The synaptic pathology of schizophrenia: Is aberrant neurodevelopment and plasticity to blame? International Review of Neurobiology, 59, 47–72. doi:10.1016/S0074-7742(04)59003-7.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., Burnet, P. W., & Harrison, P. J. (1995). Altered synaptophysin expression as a marker of synaptic pathology in schizophrenia. Neuroscience, 66, 309–319. doi:10.1016/0306–4522(94)00586-T.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., Cairns, N. J., & Harrison, P. J. (2000). Synaptophysin gene expression in schizophrenia. Investigation of synaptic pathology in the cerebral cortex. The British Journal of Psychiatry, 176, 236–242. doi:10.1192/bjp.176.3.236.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., & Harrison, P. J. (1995). Decreased synaptophysin in the medial temporal lobe in schizophrenia demonstrated using immunoautoradiography. Neuroscience, 69, 339–343. doi:10.1016/0306–4522(95)00324-C.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., & Harrison, P. J. (2001). Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Research Bulletin, 55, 569–578. doi:10.1016/S0361-9230(01)00530-5.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., & Harrison, P. J. (2005). Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: Further evidence for a synaptic pathology affecting glutamate neurons. Schizophrenia Research, 73, 159–172. doi:10.1016/j.schres.2004.05.010.

    Article  PubMed  CAS  Google Scholar 

  • Eastwood, S. L., Heffernan, J., & Harrison, P. J. (1997). Chronic haloperidol treatment differentially affects the expression of synaptic and neuronal plasticity-associated genes. Molecular Psychiatry, 2, 322–329. doi:10.1038/sj.mp.4000238.

    Article  PubMed  CAS  Google Scholar 

  • Frankle, W. G., Lerma, J., & Laruelle, M. (2003). The synaptic hypothesis of schizophrenia. Neuron, 39, 205–216. doi:10.1016/S0896-6273(03)00423-9.

    Article  PubMed  CAS  Google Scholar 

  • Gabriel, S. M., Haroutunian, V., Powchik, P., Honer, W. G., Davidson, M., Davies, P., et al. (1997). Increased concentrations of presynaptic proteins in the cingulate cortex of subjects with schizophrenia. Archives of General Psychiatry, 54, 559–566.

    PubMed  CAS  Google Scholar 

  • Glantz, L. A., Austin, M. C., & Lewis, D. A. (2000). Normal cellular levels of synaptophysin mRNA expression in the prefrontal cortex of subjects with schizophrenia. Biological Psychiatry, 48, 389–397. doi:10.1016/S0006-3223(00)00923-9.

    Article  PubMed  CAS  Google Scholar 

  • Glantz, L. A., Gilmore, J. H., Lieberman, J. A., & Jarskog, L. F. (2006). Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophrenia Research, 81, 47–63. doi:10.1016/j.schres.2005.08.014.

    Article  PubMed  Google Scholar 

  • Glantz, L. A., & Lewis, D. A. (1997). Reduction of synaptophysin immunoreactivity in the prefrontal cortex of subjects with schizophrenia. Regional and diagnostic specificity. Archives of General Psychiatry, 54, 943–952 corrected and republished article originally appeared in Arch Gen Psychiatry 1997 Jul; 54(7), 660–9.

    PubMed  CAS  Google Scholar 

  • Gogelein, H., Hartung, J., & Englert, H. C. (1999). Molecular basis, pharmacology and physiological role of cardiac K(ATP) channels. Cellular Physiology and Biochemistry, 9, 227–241. doi:10.1159/000016319.

    Article  PubMed  CAS  Google Scholar 

  • Golan, H., & Huleihel, M. (2006). The effect of prenatal hypoxia on brain development: Short- and long-term consequences demonstrated in rodent models. Developmental Science, 9, 338–349. doi:10.1111/j.1467-7687.2006.00498.x.

    Article  PubMed  Google Scholar 

  • Gross, J., Lun, A., & Berndt, C. (1993). Early postnatal hypoxia induces long-term changes in the dopaminergic system in rats. Journal of Neural Transmission, 93, 109–121. doi:10.1007/BF01245341.

    Article  PubMed  CAS  Google Scholar 

  • Halim, N. D., Weickert, C. S., McClintock, B. W., Hyde, T. M., Weinberger, D. R., Kleinman, J. E., et al. (2003). Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. Molecular Psychiatry, 8, 797–810.. doi:10.1038/sj.mp.4001319.

    Article  PubMed  CAS  Google Scholar 

  • Hermans, R. H., & Longo, L. D. (1994). Altered catecholaminergic behavioral and hormonal responses in rats following early postnatal hypoxia. Physiology & Behavior, 55, 469–475. doi:10.1016/0031-9384(94)90102-3.

    Article  CAS  Google Scholar 

  • Hoeger, H., Engelmann, M., Bernert, G., Seidl, R., Bubna-Littitz, H., Mosgoeller, W., et al. (2000). Long term neurological and behavioral effects of graded perinatal asphyxia in the rat. Life Sciences, 66, 947–962. doi:10.1016/S0024-3205(99)00678-5.

    Article  PubMed  CAS  Google Scholar 

  • Honer, W. G., Falkai, P., Chen, C., Arango, V., Mann, J. J., & Dwork, A. J. (1999). Synaptic and plasticity-associated proteins in anterior frontal cortex in severe mental illness. Neuroscience, 91, 1247–1255. doi:10.1016/S0306-4522(98)00679-4.

    Article  PubMed  CAS  Google Scholar 

  • Jay, T. M., Rocher, C., Hotte, M., Naudon, L., Gurden, H., & Spedding, M. (2004). Plasticity at hippocampal to prefrontal cortex synapses is impaired by loss of dopamine and stress: Importance for psychiatric diseases. Neurotoxicity Research, 6, 233–244.

    Article  PubMed  Google Scholar 

  • Juarez, I., Silva-Gomez, A. B., Peralta, F., & Flores, G. (2003). Anoxia at birth induced hyperresponsiveness to amphetamine and stress in postpubertal rats. Brain Research, 992, 281–287. doi:10.1016/j.brainres.2003.08.060.

    Article  PubMed  CAS  Google Scholar 

  • Kozlovsky, N., Belmaker, R. H., & Agam, G. (2000a). Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. The American Journal of Psychiatry, 157, 831–833. doi:10.1176/appi.ajp.157.5.831.

    Article  PubMed  CAS  Google Scholar 

  • Kozlovsky, N., Belmaker, R. H., & Agam, G. (2000b). Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. The American Journal of Psychiatry, 157, 831–833. doi:10.1176/appi.ajp.157.5.831.

    Article  PubMed  CAS  Google Scholar 

  • Kunugi, H., Nanko, S., & Murray, R. M. (2001). Obstetric complications and schizophrenia: Prenatal underdevelopment and subsequent neurodevelopmental impairment. The British Journal of Psychiatry Supplement, 40, s25–s29. doi:10.1192/bjp.178.40.s25.

    Article  PubMed  CAS  Google Scholar 

  • Landen, M., Davidsson, P., Gottfries, C. G., Grenfeldt, B., Stridsberg, M., & Blennow, K. (1999). Reduction of the small synaptic vesicle protein synaptophysin but not the large dense core chromogranins in the left thalamus of subjects with schizophrenia. Biological Psychiatry, 46, 1698–1702. doi:10.1016/S0006-3223(99)00160-2.

    Article  PubMed  Google Scholar 

  • Lidow, M. S., Song, Z. M., Castner, S. A., Allen, P. B., Greengard, P., & Goldman-Rakic, P. S. (2001). Antipsychotic treatment induces alterations in dendrite- and spine-associated proteins in dopamine-rich areas of the primate cerebral cortex. Biological Psychiatry, 49, 1–12. doi:10.1016/S0006-3223(00)01058-1.

    Article  PubMed  CAS  Google Scholar 

  • Lun, A., Berndt, C., Gross, J., Fischer, H. D., Bergstrasser, E., & Scheller, D. (1993). Long-term effects of postnatal hypoxia and flunarizine on the dopaminergic system. Pharmacology, Biochemistry, and Behavior, 46, 867–871. doi:10.1016/0091-3057(93)90215-F.

    Article  PubMed  CAS  Google Scholar 

  • Lun, A., Dominick, B., & Gross, J. (1990). An animal model of perinatal hypoxic brain damage: Behavioural aspects. Biomedica Biochimica Acta, 49, 1021–1026.

    PubMed  CAS  Google Scholar 

  • Mukaetova-Ladinska, E. B., Hurt, J., Honer, W. G., Harrington, C. R., & Wischik, C. M. (2002). Loss of synaptic but not cytoskeletal proteins in the cerebellum of chronic schizophrenics. Neuroscience Letters, 317, 161–165. doi:10.1016/S0304-3940(01)02458-2.

    Article  PubMed  CAS  Google Scholar 

  • Nakajima, W., Ishida, A., & Takada, G. (1999). Anoxic and hypoxic immature rat model for measurement of monoamine using in vivo microdialysis. Brain Research Brain Research Protocols, 3, 252–256. doi:10.1016/S1385-299X(98)00046-4.

    Article  PubMed  CAS  Google Scholar 

  • Nyakas, C., Buwalda, B., & Luiten, P. G. (1996). Hypoxia and brain development. Progress in Neurobiology, 49, 1–51.

    PubMed  CAS  Google Scholar 

  • Olson, E. E., & McKeon, R. J. (2004). Characterization of cellular and neurological damage following unilateral hypoxia/ischemia. Journal of the Neurological Sciences, 227, 7–19. doi:10.1016/j.jns.2004.07.021.

    Article  PubMed  CAS  Google Scholar 

  • Powell, C. M., & Miyakawa, T. (2006). Schizophrenia-relevant behavioral testing in rodent models: A uniquely human disorder? Biological Psychiatry, 59(12), 1198–1207. doi:10.1016/j.biopsych.2006.05.008.

    Article  PubMed  CAS  Google Scholar 

  • Rees, S., & Inder, T. (2005). Fetal and neonatal origins of altered brain development. Early Human Development, 81, 753–761. doi:10.1016/j.earlhumdev.2005.07.004.

    Article  PubMed  Google Scholar 

  • Sawada, K., Barr, A. M., Nakamura, M., Arima, K., Young, C. E., Dwork, A. J., et al. (2005). Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Archives of General Psychiatry, 62, 263–272. doi:10.1001/archpsyc.62.3.263.

    Article  PubMed  CAS  Google Scholar 

  • Stephan, K. E., Baldeweg, T., & Friston, K. J. (2006). Synaptic plasticity and dysconnection in schizophrenia. Biological Psychiatry, 59, 929–939. doi:10.1016/j.biopsych.2005.10.005.

    Article  PubMed  CAS  Google Scholar 

  • Thompson, P. M., Egbufoama, S., & Vawter, M. P. (2003a). SNAP-25 reduction in the hippocampus of patients with schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 27, 411–417. doi:10.1016/S0278-5846(03)00027-7.

    Article  CAS  Google Scholar 

  • Thompson, P. M., Kelley, M., Yao, J., Tsai, G., & van Kammen, D. P. (2003b). Elevated cerebrospinal fluid SNAP-25 in schizophrenia. Biological Psychiatry, 53, 1132–1137. doi:10.1016/S0006-3223(02)01599-8.

    Article  PubMed  CAS  Google Scholar 

  • Tian, S. Y., Wang, J. F., Bezchlibnyk, Y. B., & Young, L. T. (2007). Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia. Neuroscience Letters, 411, 123–127. doi:10.1016/j.neulet.2006.10.031.

    Article  PubMed  CAS  Google Scholar 

  • Vawter, M. P., Thatcher, L., Usen, N., Hyde, T. M., Kleinman, J. E., & Freed, W. J. (2002). Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Molecular Psychiatry, 7, 571–578. doi:10.1038/sj.mp.4001158.

    Article  PubMed  CAS  Google Scholar 

  • Verdoux, H., & Sutter, A. L. (2002). Perinatal risk factors for schizophrenia: Diagnostic specificity and relationships with maternal psychopathology. American Journal of Medical Genetics, 114, 898–905. doi:10.1002/ajmg.10906.

    Article  PubMed  Google Scholar 

  • Wei, J., & Hemmings, G. P. (2000). Searching for a locus for schizophrenia within chromosome Xp11. American Journal of Medical Genetics, 96, 4–7. doi:10.1002/(SICI)1096-8628(20000207)96:1<4::AID-AJMG2>3.0.CO;2-Z.

    Article  PubMed  CAS  Google Scholar 

  • Weickert, C. S., Webster, M. J., Hyde, T. M., Herman, M. M., Bachus, S. E., Bali, G., et al. (2001). Reduced GAP-43 mRNA in dorsolateral prefrontal cortex of patients with schizophrenia. Cerebral Cortex (New York, N.Y.: 1991), 11, 136–147. doi:10.1093/cercor/11.2.136.

    Article  CAS  Google Scholar 

  • Weitzdoerfer, R., Pollak, A., & Lubec, B. (2004). Perinatal asphyxia in the rat has lifelong effects on morphology, cognitive functions, and behavior. Seminars in Perinatology, 28, 249–256. doi:10.1053/j.semperi.2004.08.001.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Psychiatry Research Unit, Faculty of Health Science, Ben-Gurion University of the Negev, Beersheva, Israel

    Carmit Nadri & Galila Agam

  2. Psychiatry Research Unit, Mental Health Center, P.O. Box 4600, Beersheva, 84170, Israel

    Carmit Nadri & Galila Agam

Authors
  1. Carmit Nadri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Galila Agam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Galila Agam.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nadri, C., Agam, G. Perinatal Oxygen Restriction Does Not Result in Reduced Rat Frontal Cortex Synaptophysin Protein Levels at Adulthood as Opposed to Postmortem Findings in Schizophrenia. J Mol Neurosci 37, 60–66 (2009). https://doi.org/10.1007/s12031-008-9120-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-008-9120-4

Keywords

Search

Navigation