Skip to main content
SpringerLink
Log in

Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia

  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Microarray expression studies have reported decreased mRNA expression of histidine triad nucleotide-binding protein (HINT1) and cytosolic malate dehydrogenase (MDH1) in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia. Microarray results for neuroserpin (SERPINI1) mRNA in the DLPFC have reported increased and decreased expression in individuals with schizophrenia. The relative abundances of HINT1, MDH1, and SERPINI1 mRNA in the DLPFC in individuals with schizophrenia and controls were measured by real-time quantitative polymerase chain reaction (Q-PCR) and for HINT1 expression by in situ hybridization. The Q-PCR results were compared by analysis of covariance between individuals with schizophrenia and controls. Gene expression levels for HINT1, MDH1, and SERPINI1 were significantly different between the groups. The male individuals with schizophrenia compared to male controls showed reductions by 2.8- to 3.7-fold of HINT1, neuroserpin, and MDH1 by Q-PCR. The decreases in mRNA abundance for MDH1 (P = 5 0.006), HINT1 (P = 5 0.050), and neuroserpin (P = 5 0.005) in DLPFC of male individuals with schizophrenia is consistent with prior reports. HINT1 mRNA was reduced significantly by 34% in layer VI. Though there were no significant interactions with gender, gene expression between female patients and the female control group did not differ. These results confirm earlier reports and suggest abnormalities of specific genes related to metabolic and protease activities in the DLPFC might be considered as part of a molecular pathway in male patients with schizophrenia.

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

Similar content being viewed by others

References

  1. Bunney, W. E., Bunney, B. G., Vawter, M. P., Tomita, H., Li, J., Evans, S. J., Choudary, P. V., Myers, R. M., Jones, E. G., Watson, S. J., and Akil, H. 2003. Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders. Am. J. Psychiatry 160:657–66.

    PubMed  Google Scholar 

  2. Pongrac, J., Middleton, F. A., Lewis, D. A., Levitt, P., and Mirnics, K. 2002. Gene expression profiling with DNA microarrays: advancing our understanding of psychiatric disorders. Neurochem. Res. 27:1049–63.

    PubMed  Google Scholar 

  3. Bahn, S., Augood, S. J., Ryan, M., Standaert, D. G., Starkey, M., and Emson, P. C. 2001. Gene expression profiling in the postmortem human brain—no cause for dismay. J. Chem. Neuroanat. 22:79–94.

    PubMed  Google Scholar 

  4. Hakak, Y., Walker, J. R., Li, C., Wong, W. H., Davis, K. L., Buxbaum, J. D., Haroutunian, V., and Fienberg, A. A. 2001. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc. Natl. Acad. Sci. USA 98:4746–51.

    PubMed  Google Scholar 

  5. Hemby, S. E., Ginsberg, S. D., Brunk, B., Arnold, S. E., Trojanowski, J. Q., and Eberwine, J. H. 2002. Gene expression profile for schizophrenia: discrete neuron transcription patterns in the entorhinal cortex. Arch. Gen. Psychiatry 59:631–40.

    PubMed  Google Scholar 

  6. Middleton, F. A., Mirnics, K., Pierri, J. N., Lewis, D. A., and Levitt, P. 2002. Gene expression profiling reveals alterations of specific metabolic pathways in schizophrenia. J. Neurosci. 22:2718–29.

    PubMed  Google Scholar 

  7. Mirnics, K., Middleton, F. A., Lewis, D. A., and Levitt, P. 2001. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci. 24:479–86.

    PubMed  Google Scholar 

  8. Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A., and Levitt, P. 2000. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28:53–67.

    PubMed  Google Scholar 

  9. Mirnics, K., Middleton, F. A., Stanwood, G. D., Lewis, D. A., and Levitt, P. 2001. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol. Psychiatry 6:293–301.

    PubMed  Google Scholar 

  10. Vawter, M. P., Barrett, T., Cheadle, C., Sokolov, B. P., Wood, W. H., 3rd, Donovan, D. M., Webster, M., Freed, W. J., and Becker, K. G. 2001. Application of cDNA microarrays to examine gene expression differences in schizophrenia. Brain Res. Bull. 55:641–50.

    PubMed  Google Scholar 

  11. Vawter, M. P., Crook, J. M., Hyde, T. M., Kleinman, J. E., Weinberger, D. R., Becker, K. G., and Freed, W. J. 2002. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study. Schizophr. Res. 58:11–20.

    PubMed  Google Scholar 

  12. Lehrmann, E., Oyler, J., Vawter, M. P., Hyde, T. M., Kolachana, B., Kleinman, J. E., Huestis, M. A., Becker, K. G., and Freed, W. J. 2003. Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 3:27–40.

    PubMed  Google Scholar 

  13. Yuen, T., Wurmbach, E., Pfeffer, R. L., Ebersole, B. J., and Sealfon, S. C. 2002. Accuracy and calibration of commercial oligonucleotide and custom cDNA microarrays. Nucleic Acids Res. 30(10):e48.

    PubMed  Google Scholar 

  14. Mimmack, M. L., Ryan, M., Baba, H., Navarro-Ruiz, J., Iritani, S., Faull, R. L., McKenna, P. J., Jones, P. B., Arai, H., Starkey, M., Emson, P. C., and Bahn, S. 2002. Gene expression analysis in schizophrenia: reproducible up-regulation of several members of the apolipoprotein L family located in a high-susceptibility locus for schizophrenia on chromosome 22. Proc. Natl. Acad. Sci. USA 99(7):4680–5.

    PubMed  Google Scholar 

  15. American Psychiatric Association. 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Association, Washington, DC.

  16. Johnston, N. L., Cervenak, J., Shore, A. D., Torrey, E. F., Yolken, R. H., and Cerevnak, J. 1997. Multivariate analysis of RNA levels from postmortem human brains as measured by three different methods of RT-PCR. Stanley Neuropathology Consortium. J. Neurosci. Methods 77:83–92.

    PubMed  Google Scholar 

  17. Webster, M. J., Shannon Weickert, C., Herman, M. M., Hyde, T. M., and Kleinman, J. E. 2001. Synaptophysin and GAP-43 mRNA levels in the hippocampus of subjects with schizophrenia. Schizophr. Res. 49:89–98.

    PubMed  Google Scholar 

  18. Hastings, G. A., Coleman, T. A., Haudenschild, C. C., Stefansson, S., Smith, E. P., Barthlow, R., Cherry, S., Sandkvist, M., and Lawrence, D. A. 1997. Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons. Implications for the regulation of motor learning and neuronal survival. J. Biol. Chem. 272:33062–7.

    PubMed  Google Scholar 

  19. Brenner, C. 2002. Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases. Biochemistry 41:9003–14.

    PubMed  Google Scholar 

  20. Korsisaari, N., Rossi, D. J., Luukko, K., Huebner, K., Henkemeyer, M., Makela, T. P. 2003. The histidine triad protein Hint is not required for murine development or Cdk7 function. Mol. Cell. Biol. 23:3929–35.

    PubMed  Google Scholar 

  21. Bieganowski, P., Garrison, P. N., Hodawadekar, S. C., Faye, G., Barnes, L. D., and Brenner, C. 2002. Adenosine monophosphoramidase activity of Hint and Hnt1 supports function of Kin28, Ccll, and Tfb3. J. Biol. Chem. 277:10852–60.

    PubMed  Google Scholar 

  22. Shiekhattar, R., Mermelstein, F., Fisher, R. P., Drapkin, R., Dynlacht, B., Wessling, H. C., Morgan, D. O., and Reinberg, D. 1995. Cdk-activating kinase complex is a component of human transcription factor TFIIH. Nature 374:283–7.

    PubMed  Google Scholar 

  23. Brenner, C., Bieganowski, P., Pace, H. C., and Huebner, K. 1999. The histidine triad superfamily of nucleotide-binding proteins. J. Cell. Physiol. 181:179–87.

    PubMed  Google Scholar 

  24. Brenner, C., Garrison, P., Gilmour, J., Peisach, D., Ringe, D., Petsko, G. A., and Lowenstein, J. M. 1997. Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins. Nat. Struct. Biol. 4:231–8.

    PubMed  Google Scholar 

  25. Camp, N. J., Neuhausen, S. L., Tiobech, J., Polloi, A., Coon, H., and Myles-Worsley, M. 2001. Genomewide multipoint linkage analysis of seven extended Palauan pedigrees with schizophrenia, by a Markov-chain Monte Carlo method. Am. J. Hum. Genet. 69:1278–89.

    PubMed  Google Scholar 

  26. Coon, H., Myles-Worsley, M., Tiobech, J., Hoff, M., Rosenthal, J., Bennett, P., Reimherr, F., Wender, P., Dale, P., Polloi, A., and Byerley, W. 1998. Evidence for a chromosome 2p13-14 schizophrenia susceptibility locus in families from Palau, Micronesia. Mol. Psychiatry 3:521–7.

    PubMed  Google Scholar 

  27. Liu, J., Juo, S. H., Dewan, A., Grunn, A., Tong, X., Brito, M., Park, N., Loth, J. E., Kanyas, K., Lerer, B., Endicott, J., Penchaszadeh, G., Knowles, J. A., Ott, J., Gilliam, T. C., and Baron, M. 2003. Evidence for a putative bipolar disorder locus on 2p13-16 and other potential loci on 4q31, 7q34, 8q13, 9q31, 10q21-24, 13q32, 14q21 and 17q11-12. Mol. Psychiatry 8:333–42.

    PubMed  Google Scholar 

  28. Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, L. E., Straub, R. E., Hovatta, I., Williams, N. M., Schwab, S. G., Pulver, A. E., Faraone, S. V., Brzustowicz, L. M., Kaufmann, C. A., Garver, D. L., Gurling, H. M., Lindholm, E., Coon, H., Moises, H. W., Byerley, W., Shaw, S. H., Mesen, A., Sherrington, R., O'Neill, F. A., Walsh, D., Kendler, K. S., Ekelund, J., Paunio, T., Lonnqvist, J., Peltonen, L., O'Donovan, M. C., Owen, M. J., Wildenauer, D. B., Maier, W., Nestadt, G., Blouin, J. L., Antonarakis, S. E., Mowry, B. J., Silverman, J. M., Crowe, R. R., Cloninger, C. R., Tsuang, M. T., Malaspina, D., Harkavy-Friedman, J. M., Svrakic, D. M., Bassett, A. S., Holcomb, J., Kalsi, G., McQuillin, A., Brynjolfson, J., Sigmundsson, T., Petursson, H., Jazin, E., Zoega, T., and Helgason, T. 2003. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am. J. Hum. Genet. 73:34–48.

    PubMed  Google Scholar 

  29. Kuo, W. P., Jenssen, T. K., Butte, A. J., Ohno-Machado, L., and Kohane, I. S. 2002. Analysis of matched mRNA measurements from two different microarray technologies. Bioinformatics 18:405–12.

    PubMed  Google Scholar 

  30. Osterwalder, T., Contartese, J., Stoeckli, E. T., Kuhn, T. B., and Sonderegger, P. 1996. Neuroserpin, an axonally secreted serine protease inhibitor. EMBO J. 15:2944–53.

    PubMed  Google Scholar 

  31. Schrimpf, S. P., Bleiker, A. J., Brecevic, L., Kozlov, S. V., Berger, P., Osterwalder, T., Krueger, S. R., Sehinzel, A., and Sonderegger, P. 1997. Human neuroserpin (PI12): cDNA cloning and chromosomal localization to 3q26. Genomics 40:55–62.

    PubMed  Google Scholar 

  32. Davis, R. L., Holohan, P. D., Shrimpton, A. E., Tatum, A. H., Daucher, J., Collins, G. H., Todd, R., Bradshaw, C., Kent, P., Feiglin, D., Rosenbaum, A., Yerby, M. S., Shaw, C. M., Lacbawan, F., and Lawrence, D. A. 1999. Familial encephalopathy with neuroserpin inclusion bodies. Am. J. Pathol. 155:1901–13.

    PubMed  Google Scholar 

  33. Davis, R. L., Shrimpton, A. E., Holohan, P. D., Bradshaw, C., Feiglin, D., Collins, G. H., Sonderegger, P., Kinter, J., Becker, L. M., Lacbawan, F., Krasnewich, D., Muenke, M., Lawrence, D. A., Yerby, M. S., Shaw, C. M., Gooptu, B., Elliott, P. R., Finch, J. T., Carrell, R. W., and Lomas, D. A. 1999. Familial dementia caused by polymerization of mutant neuroserpin. Nature 401:376–9.

    PubMed  Google Scholar 

  34. Hoffman, K. B., Martinez, J., and Lynch, G. 1998. Proteolysis of cell adhesion molecules by serine proteases: a role in long term potentiation? Brain Res. 811:29–33.

    PubMed  Google Scholar 

  35. Vawter, M. P., Usen, N., Thatcher, L., Ladenheim, B., Zhang, P., VanderPutten, D. M., Conant, K., Herman, M. M., van Kammen, D. P., Sedvall, G., Garver, D. L., and Freed, W. J. 2001. Characterization of human cleaved N-CAM and association with schizophrenia. Exp. Neurol. 172:29–46.

    PubMed  Google Scholar 

  36. Xu, J., Burgoyne, P. S., and Arnold, A. P. 2002. Sex differences in sex chromosome gene expression in mouse brain. Hum. Mol. Genet. 11:1409–19.

    PubMed  Google Scholar 

  37. Flor-Henry, P. 1990. Influence of gender in schizophrenia as related to other psychopathological syndromes. Schizophr. Bull. 16:211–27.

    PubMed  Google Scholar 

  38. Goldstein, J. M., Seidman, L. J., Horton, N. J., Makris, N., Kennedy, D. N., Caviness, V. S., Jr., Faraone, S. V., and Tsuang, M. T. 2001. Normal sexual dimorphism of the adult human brain assessed by in vivo magnetic resonance imaging. Cereb. Cortex 11:490–7.

    PubMed  Google Scholar 

  39. Andreasen, N. C., Swayze, V. W. D., Flaum, M., Yates, W. R., Arndt, S., and McChesney, C. 1990. Ventricular enlargement in schizophrenia evaluated with computed tomographic scanning. Effects of gender, age, and stage of illness. Arch. Gen. Psychiatry 47:1008–15.

    PubMed  Google Scholar 

  40. Swaab, D. F., Chung, W. C. J., Kruijvera, F. P. M., Hofman, M. A., and Ishuninac, T. A. 2001. Structural and functional sex differences in the human hypothalamus. Hormones and Behavior 40:93–98.

    PubMed  Google Scholar 

  41. Devlin, B., Bacanu, S. A., Roeder, K., Reimherr, F., Wender, P., Galke, B., Novasad, D., Chu, A., K, T. C., Tiobek, S., Otto, C., and Byerley, W. 2002. Genome-wide multipoint linkage analyses of multiplex schizophrenia pedigrees from the oceanic nation of Palau. Mol. Psychiatry 7:689–94.

    PubMed  Google Scholar 

  42. Paunio, T., Ekelund, J., Varilo, T., Parker, A., Hovatta, I., Turunen, J. A., Rinard, K., Foti, A., Terwilliger, J. D., Juvonen, H., Suvisaari, J., Arajarvi, R., Suokas, J., Partonen, T., Lonnqvist, J., Meyer, J., and Peltonen, L. 2001. Genome-wide scan in a nationwide study sample of schizophrenia families in Finland reveals susceptibility loci on chromosomes 2q and 5q. Hum. Mol. Genet. 10:3037–48.

    PubMed  Google Scholar 

  43. Straub, R. E., MacLean, C. J., Ma, Y., Webb, B. T., Myakishev, M. V., Harris-Kerr, C., Wormely, B., Sadek, H., Kadambi, B., O'Neill, F. A., Walsh, D., and Kendler, K. S. 2002. Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes. Mol. Psychiatry 7:542–59.

    PubMed  Google Scholar 

  44. McGuffin, P., Owen, M. J., and Farmer, A. E. 1995. Genetic basis of schizophrenia. Lancet 346:678–82.

    PubMed  Google Scholar 

  45. Davidson, L. L. and Heinrichs, R. W. 2003. Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Psychiatry Res. 122:69–87.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Human Behavior, College of Medicine, University of California, Irvine, California

    Marquis P. Vawter, Erick Ferran, Kevin Overman & William E. Bunney

  2. National Institutes of Health, National Institute of Mental Health, Clinical Brain Disorders Branch, Bethesda, Maryland

    Cynthia Shannon Weickert, Mitsuyuki Matsumoto, Thomas M. Hyde, Daniel R. Weinberger & Joel E. Kleinman

Authors
  1. Marquis P. Vawter
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia Shannon Weickert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erick Ferran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitsuyuki Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin Overman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas M. Hyde
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel R. Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. William E. Bunney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joel E. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marquis P. Vawter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vawter, M.P., Weickert, C.S., Ferran, E. et al. Gene Expression of Metabolic Enzymes and a Protease Inhibitor in the Prefrontal Cortex Are Decreased in Schizophrenia. Neurochem Res 29, 1245–1255 (2004). https://doi.org/10.1023/B:NERE.0000023611.99452.47

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:NERE.0000023611.99452.47

Search

Navigation