Skip to main content
SpringerLink
Log in

Glutathione Deficit and Redox Dysregulation in Animal Models of Schizophrenia

  • Protocol
  • First Online:
Animal Models of Schizophrenia and Related Disorders

Part of the book series: Neuromethods ((NM,volume 59))

Abstract

Evidence of altered antioxidant systems and signs of elevated oxidative stress are reported in peripheral tissue and brain of schizophrenic patients, including low levels of glutathione (GSH), a major thiol antioxidant and redox buffer. Functional and genetic data indicate that an impaired regulation of GSH synthesis is a vulnerability factor for the disease. Impaired GSH synthesis from a genetic origin combined with environmental risk factors generating oxidative stress (e.g., malnutrition, exposure to toxins, maternal infection and diabetes, obstetrical complications, and psychological stress) could lead to redox dysregulation. This could subsequently perturb normal brain development and maturation with delayed functional consequences emerging in early adulthood. Depending on the nature and the time of occurrence of the environmental insults, the structural and functional delayed consequences could vary, giving rise to various endophenotypes. The use of animal models of GSH deficit represents a valuable approach to investigate how interactions between genetic and environmental factors lead to the emergence of pathologies found in the disease. Moreover, these models of GSH can be useful to investigate links between schizophrenia and comorbid somatic disorders, as dysregulation of the GSH system and elevated oxidative stress are also found in cardiovascular diseases and diabetes. This chapter reviews pharmacological and genetic rodent models of GSH synthesis dysregulation used to address some of the aforementioned issues. Up to date, these models revealed that GSH deficits lead to morphological, physiological, and behavioral alterations that are quite analogous to pathologies observed in patients. This includes hypofunction of NMDA receptors, alteration of dopamine neurotransmission, anomalies in parvalbumin-immunoreactive fast-spiking interneurons, and reduced myelination. In addition, a GSH deficit affects the brain in a region-specific manner, the anterior cingulate cortex and the ventral hippocampus being the most vulnerable regions investigated. Interestingly, a GSH deficit during a limited period of postnatal development is sufficient to have long-lasting consequences on the integrity of PV–IR interneurons in the anterior cingulate cortex and impairs cognitive functions in adulthood. Finally, these animal models of GSH deficit display behavioral impairments that could be related to schizophrenia. Altogether, current data strongly support a contributing role of a redox dysregulation on the development of pathologies associated with the illness and demonstrate the usefulness of these models to better understand the biological mechanisms leading to schizophrenia.

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

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39, 44–84.

    PubMed  CAS  Google Scholar 

  2. Jones, D. P. (2008) Radical-free biology of oxidative stress. Am J Physiol Cell Physiol 295, C849–C868.

    PubMed  CAS  Google Scholar 

  3. Kwon, Y. W., Masutani, H., Nakamura, H., Ishii, Y., and Yodoi, J. (2003) Redox regulation of cell growth and cell death. Biol Chem 384, 991–996.

    PubMed  CAS  Google Scholar 

  4. Menon, S. G. and Goswami, P. C. (2007) A redox cycle within the cell cycle: ring in the old with the new. Oncogene 26, 1101–1109.

    PubMed  CAS  Google Scholar 

  5. Shi, Z. Z., Osei-Frimpong, J., Kala, G., Kala, S. V., Barrios, R. J., Habib, G. M., Lukin, D. J., Danney, C. M., Matzuk, M. M., and Lieberman, M. W. (2000) Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc Natl Acad Sci USA 97, 5101–5106.

    PubMed  CAS  Google Scholar 

  6. Lipton, S. A., Choi, Y. B., Takahashi, H., Zhang, D., Li, W., Godzik, A., and Bankston, L. A. (2002) Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation. Trends Neurosci 25, 474–480.

    PubMed  CAS  Google Scholar 

  7. Lu, S. C. (2009) Regulation of glutathione synthesis. Mol Aspects Med 30, 42–59.

    PubMed  CAS  Google Scholar 

  8. Forman, H. J., Zhang, H., and Rinna, A. (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30, 1–12.

    PubMed  CAS  Google Scholar 

  9. Dringen, R. (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62, 649–671.

    PubMed  CAS  Google Scholar 

  10. Herken, H., Uz, E., Ozyurt, H., Sogut, S., Virit, O., and Akyol, O. (2001) Evidence that the activities of erythrocyte free radical scavenging enzymes and the products of lipid peroxidation are increased in different forms of schizophrenia. Mol Psychiatry 6, 66–73.

    PubMed  CAS  Google Scholar 

  11. Khan, M. M., Evans, D. R., Gunna, V., Scheffer, R. E., Parikh, V. V., and Mahadik, S. P. (2002) Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophr Res 58, 1–10.

    PubMed  Google Scholar 

  12. Reddy, R., Keshavan, M., and Yao, J. K. (2003) Reduced plasma antioxidants in first-episode patients with schizophrenia. Schizophr Res 62, 205–212.

    PubMed  Google Scholar 

  13. Yao, J. K., Reddy, R., and van Kammen, D. P. (2000) Abnormal age-related changes of plasma antioxidant proteins in schizophrenia. Psychiatry Res 97, 137–151.

    PubMed  CAS  Google Scholar 

  14. Mahadik, S. P. and Mukherjee, S. (1996). Free radical pathology and antioxidant defense in schizophrenia: a review. Schizophr Res 19, 1–17.

    PubMed  CAS  Google Scholar 

  15. Raffa, M., Mechri, A., Othman, L. B., Fendri, C., Gaha, L., and Kerkeni, A. (2009) Decreased glutathione levels and antioxidant enzyme activities in untreated and treated schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry. doi:10.1016/j.pnpbp.2009.06.018.

    Google Scholar 

  16. Yao, J. K., Reddy, R. D., and van Kammen, Ds. P. (2001) Oxidative damage and schizophrenia: an overview of the evidence and its therapeutic implications. CNS Drugs 15, 287–310.

    PubMed  CAS  Google Scholar 

  17. Zhang, X. Y., Tan, Y. L., Cao, L. Y., Wu, G. Y., Xu, Q., Shen, Y., and Zhou, D. F. (2006) Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res 81, 291–300.

    PubMed  Google Scholar 

  18. Do, K. Q., Bovet, P., Cabungcal, J. H., Conus, P., Gysin, R., Lavoie, S., Steullet, P., and Cuenod, M. (2009) Redox dysregulation in schizophrenia: genetic susceptibility and pathophysiological mechanisms. In Handbook of Neurochemistry and Molecular Neurobiology, Vol: Schizophrenia (Javitt, D. C., Kantrowitz, I. T., Lajtha, A., Eds.), Springer, New York, vol. 27, pp. 285–311.

    Google Scholar 

  19. Keshavan, M. S., Mallinger, A. G., Pettegrew, J. W., and Dippold, C. (1993) Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res 49, 89–95.

    PubMed  CAS  Google Scholar 

  20. Reddy, R. D., Keshavan, M. S., and Yao, J. K. (2004) Reduced red blood cell membrane essential polyunsaturated fatty acids in first episode schizophrenia at neuroleptic-naive baseline. Schizophr Bull 30, 901–911.

    PubMed  Google Scholar 

  21. Mahadik, S. P., Mukherjee, S., Correnti, E. E., Kelkar, H. S., Wakade, C. G., Costa, R. M., and Scheffer, R. (1994) Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. Schizophr Res 13, 239–247.

    PubMed  CAS  Google Scholar 

  22. Keshavan, M. S., Stanley, J. A., Montrose, D. M., Minshew, N. J., and Pettegrew, J. W. (2003) Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study. Mol Psychiatry 8, 316–323.

    PubMed  CAS  Google Scholar 

  23. Pettegrew, J. W., Keshavan, M. S., Panchalingam, K., Strychor, S., Kaplan, D. B., Tretta, M. G., and Allen, M. (1991) Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 48, 563–568.

    PubMed  CAS  Google Scholar 

  24. Yao, J., Stanley, J. A., Reddy, R. D., Keshavan, M. S., and Pettegrew, J. W. (2002) Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 52, 823–830.

    PubMed  CAS  Google Scholar 

  25. Do, K. Q., Trabesinger, A. H., Kirsten-Kruger, M., Lauer, C. J., Dydak, U., Hell, D., Holsboer, F., Boesiger, P., and Cuenod, M. (2000) Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci 12, 3721–3728.

    PubMed  CAS  Google Scholar 

  26. Prabakaran, S., Swatton, J. E., Ryan, M. M., Huffaker, S. J., Huang, J. T., Griffin, J. L., Wayland, M., Freeman, T., Dudbridge, F., Lilley, K. S., Karp, N. A., Hester, S., Tkachev, D., Mimmack, M. L., Yolken, R. H., Webster, M. J., Torrey, E. F., and Bahn, S. (2004) Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 9, 684–697.

    PubMed  CAS  Google Scholar 

  27. Yao, J. K., Leonard, S., and Reddy, R. (2006) Altered glutathione redox state in schizophrenia. Dis Markers 22, 83–93.

    PubMed  CAS  Google Scholar 

  28. Loven, D. P., James, J. F., Biggs, L., and Little, K. Y. (1996) Increased manganese-superoxide dismutase activity in postmortem brain from neuroleptic-treated psychotic patients. Biol Psychiatry 40, 230–232.

    PubMed  CAS  Google Scholar 

  29. Michel, T. M., Thome, J., Martin, D., Nara, K., Zwerina, S., Tatschner, T., Weijers, H. G., and Koutsilieri, E. (2004) Cu, Zn- and Mn-superoxide dismutase levels in brains of patients with schizophrenic psychosis. J Neural Transm 111, 1191–1201.

    PubMed  CAS  Google Scholar 

  30. Gysin, R., Kraftsik, R., Sandell, J., Bovet, P., Chappuis, C., Conus, P., Deppen, P., Preisig, M., Ruiz, V., Steullet, P., Tosic, M., Werge, T., Cuenod, M., and Do, K. Q. (2007) Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci USA 104, 16621–16626.

    PubMed  CAS  Google Scholar 

  31. Gysin, R., Krafsik, R., Boulat, O., Conus, P., Comte-Krieger, E., Polari, A., Steullet, P., Preisig, M.,Teichmann, T., Cuenod, M., and Do, K. Q. (2010, Oct 30) Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. Antioxid Redox Signal [Epub ahead of print].

    Google Scholar 

  32. Crow, T. J. (1986) The continuum of psychosis and its implication for the structure of the gene. Br J Psychiatry 149, 419–429.

    PubMed  CAS  Google Scholar 

  33. Berk, M., Copolov, D. L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., and Bush, A. I. (2008) N-acetyl cysteine for depressive symptoms in bipolar disorder – a double-blind randomized placebo-controlled trial. Biol Psychiatry 64, 468–475.

    PubMed  CAS  Google Scholar 

  34. Berk, M., Copolov, D., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., Judd, F., Katz, F., Katz, P., Ording-Jespersen, S., Little, J., Conus, P., Cuenod, M., Do, K. Q., and Bush, A. I. (2008) N-acetyl cysteine as a glutathione precursor for schizophrenia – a double-blind, randomized, placebo-controlled trial. Biol Psychiatry 64, 361–368.

    PubMed  CAS  Google Scholar 

  35. Lavoie, S., Murray, M. M., Deppen, P., Knyazeva, M. G., Berk, M., Boulat, O., Bovet, P., Bush, A. I., Conus, P., Copolov, D., Fornari, E., Meuli, R., Solida, A., Vianin, P., Cuenod, M., Buclin, T., and Do, K. Q. (2008) Glutathione precursor, N-acetyl-cysteine, improves mismatch negativity in schizophrenic patients. Neuropsychopharmacology 33, 2187–2199.

    PubMed  CAS  Google Scholar 

  36. Kempf, L., Nicodemus, K. K., Kolachana, B., Vakkalanka, R., Verchinski, B. A., Egan, M. F., Straub, R. E., Mattay, V. A., Callicott, J. H., Weinberger, D. R., and Meyer-Lindenberg, A. (2008) Functional polymorphisms in PRODH are associated with risk and protection for schizophrenia and fronto-striatal structure and function. PLoS Genet 4, e1000252.

    PubMed  Google Scholar 

  37. Krishnan, N., Dickman, M. B., and Becker, D. F. (2008) Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radic Biol Med 44, 671–681.

    PubMed  CAS  Google Scholar 

  38. Do, K. Q., Cabungcal, J. H., Frank, A., Steullet, P., and Cuenod, M. (2009) Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol 19, 220–230.

    PubMed  CAS  Google Scholar 

  39. Garcia-Bueno, B., Caso, J. R., and Leza, J. C. (2008) Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 32, 1136–1151.

    PubMed  CAS  Google Scholar 

  40. Paintlia, M. K., Paintlia, A. S., Khan, M., Singh, I., and Singh, A. K. (2008) Modulation of peroxisome proliferator-activated receptor-alpha activity by N-acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures. J Neurochem 105, 956–970.

    PubMed  CAS  Google Scholar 

  41. Wedner, H. J., Simchowitz, L., Stenson, W. F., and Fischman, C. M. (1981) Inhibition of human polymorphonuclear leukocyte function by 2-cyclohexene-1-one. A role for glutathione in cell activation. J Clin Invest 68, 535–543.

    PubMed  CAS  Google Scholar 

  42. Bizzozero, O. A., Ziegler, J. L., De, J. G., and Bolognani, F. (2006) Acute depletion of reduced glutathione causes extensive carbonylation of rat brain proteins. J Neurosci Res 83, 656–667.

    PubMed  CAS  Google Scholar 

  43. Gupta, A., Gupta, A., Datta, M., and Shukla, G. S. (2000) Cerebral antioxidant status and free radical generation following glutathione depletion and subsequent recovery. Mol Cell Biochem 209, 55–61.

    PubMed  CAS  Google Scholar 

  44. Dean, O., Bush, A. I., Berk, M., Copolov, D. L., and van den Buuse, M. (2009) Glutathione depletion in the brain disrupts short-term spatial memory in the Y-maze in rats and mice. Behav Brain Res 198, 258–262.

    PubMed  CAS  Google Scholar 

  45. Cruz-Aguado, R., Almaguer-Melian, W., Diaz, C. M., Lorigados, L., and Bergado, J. (2001) Behavioral and biochemical effects of glutathione depletion in the rat brain. Brain Res Bull 55, 327–333.

    PubMed  CAS  Google Scholar 

  46. Campbell, E. B., Hayward, M. L., and Griffith, O. W. (1991) Analytical and preparative separation of the diastereomers of l-buthionine (SR)-sulfoximine, a potent inhibitor of glutathione biosynthesis. Anal Biochem 194, 268–277.

    PubMed  CAS  Google Scholar 

  47. Griffith, O. W. and Meister, A. (1979) Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem 254, 7558–7560.

    PubMed  CAS  Google Scholar 

  48. Griffith, O. W. (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 27, 922–935.

    PubMed  CAS  Google Scholar 

  49. Reyes, E., Ott, S., Robinson, B., and Contreras, R. (1995) The effect of in utero administration of buthionine sulfoximine on rat development. Pharmacol Biochem Behav 50, 491–497.

    PubMed  CAS  Google Scholar 

  50. Slivka, A., Spina, M. B., Calvin, H. I., and Cohen, G. (1988) Depletion of brain glutathione in preweanling mice by l-buthionine sulfoximine. J Neurochem 50, 1391–1393.

    PubMed  CAS  Google Scholar 

  51. Castagne, V., Rougemont, M., Cuenod, M., and Do, K. Q. (2004) Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat’s development induce long-term cognitive deficit: relevance to schizophrenia. Neurobiol Dis 15, 93–105.

    PubMed  CAS  Google Scholar 

  52. Jacobsen, J. P., Rodriguiz, R. M., Mork, A., and Wetsel, W. C. (2005) Monoaminergic dysregulation in glutathione-deficient mice: possible relevance to schizophrenia? Neuroscience 132, 1055–1072.

    PubMed  CAS  Google Scholar 

  53. Martensson, J. and Meister, A. (1992) Glutathione deficiency increases hepatic ascorbic acid synthesis in adult mice. Proc Natl Acad Sci USA 89, 11566–11568.

    PubMed  CAS  Google Scholar 

  54. Nishikimi, M. and Yagi, K. (1996) Biochemistry and molecular biology of ascorbic acid biosynthesis. Subcell Biochem 25, 17–39.

    PubMed  CAS  Google Scholar 

  55. Ellender, G. and Gazelakis, T. (1996) Growth and bone remodelling in a scorbutic rat model. Aust Dent J 41, 97–106.

    PubMed  CAS  Google Scholar 

  56. Finlay, J. M. and Zigmond, M. J. (1997) The effects of stress on central dopaminergic neurons: possible clinical implications. Neurochem Res 22, 1387–1394.

    PubMed  CAS  Google Scholar 

  57. Cadet, J. L. and Brannock, C. (1998) Free radicals and the pathobiology of brain dopamine systems. Neurochem Int 32, 117–131.

    PubMed  CAS  Google Scholar 

  58. Hirrlinger, J., Schulz, J. B., and Dringen, R. (2002) Effects of dopamine on the glutathione metabolism of cultured astroglial cells: implications for Parkinson’s disease. J Neurochem 82, 458–467.

    PubMed  CAS  Google Scholar 

  59. Rabinovic, A. D. and Hastings, T. G. (1998) Role of endogenous glutathione in the oxidation of dopamine. J Neurochem 71, 2071–2078.

    PubMed  CAS  Google Scholar 

  60. Grima, G., Benz, B., Parpura, V., Cuenod, M., and Do, K.Q. (2003) Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. Schizophr Res 62, 213–224.

    PubMed  Google Scholar 

  61. Chen, N. and Reith, M. E. (2000) Structure and function of the dopamine transporter. Eur J Pharmacol 405, 329–339.

    PubMed  CAS  Google Scholar 

  62. Chan, S. W. and Reade, P. C. (1996) Determination of the l-ascorbic acid requirements in Wistar osteogenic disorder Shionogi rats for prolonged carcinogenesis experiments. Lab Anim 30, 337–346.

    PubMed  CAS  Google Scholar 

  63. Rougemont, M., Do, K. Q., and Castagne, V. (2002) New model of glutathione deficit during development: effect on lipid peroxidation in the rat brain. J Neurosci Res 70, 774–783.

    PubMed  CAS  Google Scholar 

  64. Mamiya, T., Kise, M., and Morikawa, K. (2008) Ferulic acid attenuated cognitive deficits and increase in carbonyl proteins induced by buthionine-sulfoximine in mice. Neurosci Lett 430, 115–118.

    PubMed  CAS  Google Scholar 

  65. Castagne, V., Cuenod, M., and Do, K. Q. (2004) An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development. Neuroscience 123, 821–834.

    PubMed  CAS  Google Scholar 

  66. Steullet, P., Neijt, H. C., Cuenod, M., and Do, K. Q. (2006) Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. Neuroscience 137, 807–819.

    PubMed  CAS  Google Scholar 

  67. Giblin, F. J. (2000) Glutathione: a vital lens antioxidant. J Ocul Pharmacol Ther 16, 121–135.

    PubMed  CAS  Google Scholar 

  68. Li, Z. R., Reiter, R. J., Fujimori, O., Oh, C. S., and Duan, Y. P. (1997) Cataractogenesis and lipid peroxidation in newborn rats treated with buthionine sulfoximine: preventive actions of melatonin. J Pineal Res 22, 117–123.

    PubMed  CAS  Google Scholar 

  69. Lewis, D. A. and Gonzalez-Burgos, G. (2008) Neuroplasticity of neocortical circuits in schizophrenia. Neuropsychopharmacology 33, 141–165.

    PubMed  Google Scholar 

  70. Cabungcal, J. H., Nicolas, D., Kraftsik, R., Cuenod, M., Do, K. Q., and Hornung, J. P. (2006) Glutathione deficit during development induces anomalies in the rat anterior cingulate GABAergic neurons: relevance to schizophrenia. Neurobiol Dis 22, 624–637.

    PubMed  CAS  Google Scholar 

  71. Garey, L. J., Ong, W. Y., Patel, T. S., Kanani, M., Davis, A., Mortimer, A. M., Barnes, T. R., and Hirsch, S. R. (1998) Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J Neurol Neurosurg Psychiatry 65, 446–453.

    PubMed  CAS  Google Scholar 

  72. Glantz, L. A. and Lewis, D. A. (2000) Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57, 65–73.

    PubMed  CAS  Google Scholar 

  73. Kolluri, N., Sun, Z., Sampson, A. R., and Lewis, D. A. (2005) Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am J Psychiatry 162, 1200–1202.

    PubMed  Google Scholar 

  74. Cabungcal, J. H., Preissmann, D., Delseth, C., Cuenod, M., Do, K. Q., and Schenk, F. (2007) Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: relevance to schizophrenia. Neurobiol Dis 26, 634–645.

    PubMed  CAS  Google Scholar 

  75. Preissmann, D. (2009) A la recherche de symptômes de désorientation dépendant d’un déficit d’intégration multisensorielle chez l’animal: un éclairage sur les mécanismes fondamentaux de la schizophrénie. Thesis, University of Lausanne, Lausanne, Switzerland.

    Google Scholar 

  76. Danion, J. M., Rizzo, L., and Bruant, A. (1999) Functional mechanisms underlying impaired recognition memory and conscious awareness in patients with schizophrenia. Arch Gen Psychiatry 56, 639–644.

    PubMed  CAS  Google Scholar 

  77. Heckers, S., Curran, T., Goff, D., Rauch, S. L., Fischman, A. J., Alpert, N. M., and Schacter, D. L. (2000) Abnormalities in the thalamus and prefrontal cortex during episodic object recognition in schizophrenia. Biol Psychiatry 48, 651–657.

    PubMed  CAS  Google Scholar 

  78. Laws, K. R., Leeson, V. C., and McKenna, P. J. (2006) Domain-specific deficits in schizophrenia. Cogn Neuropsychiatry 11, 537–556.

    PubMed  Google Scholar 

  79. Tek, C., Gold, J., Blaxton, T., Wilk, C., McMahon, R. P., and Buchanan, R. W. (2002) Visual perceptual and working memory impairments in schizophrenia. Arch Gen Psychiatry 59, 146–153.

    PubMed  Google Scholar 

  80. Prokai, L. and Simpkins, J. W. (2007) Structure–nongenomic neuroprotection relationship of estrogens and estrogen-derived compounds. Pharmacol Ther 114, 1–12.

    PubMed  CAS  Google Scholar 

  81. Preissmann, D., Cocchi, C., Cabungcal, J. H., and Schenk, F. (2008) Animal models of schizophrenia: in search of a common key neurological syndrome in rats and humans. In Endophenotypes of Psychiatric and Neurodegenerative Disorders in Animal Models (Granon, S., Ed.), Research Signpost/Transworld Research Network, Kerala, India, pp. 265–291.

    Google Scholar 

  82. Ross, L. A., Saint-Amour, D., Leavitt, V. M., Molholm, S., Javitt, D. C., and Foxe, J. J. (2007) Impaired multisensory processing in schizophrenia: deficits in the visual enhancement of speech comprehension under noisy environmental conditions. Schizophr Res 97, 173–183.

    PubMed  Google Scholar 

  83. Pileblad, E. and Magnusson, T. (1989) Intracerebroventricular administration of l-buthionine sulfoximine: a method for depleting brain glutathione. J Neurochem 53, 1878–1882.

    PubMed  CAS  Google Scholar 

  84. Shukitt-Hale, B., Denisova, N. A., Strain, J. G., and Joseph, J. A. (1997) Psychomotor effects of dopamine infusion under decreased glutathione conditions. Free Radic Biol Med 23, 412–418.

    PubMed  CAS  Google Scholar 

  85. Abe, K., Nakanishi, K., and Saito, H. (2000) The possible role of endogenous glutathione as an anticonvulsant in mice. Brain Res 854, 235–238.

    PubMed  CAS  Google Scholar 

  86. Shukitt-Hale, B., Erat, S. A., and Joseph, J. A. (1998) Spatial learning and memory deficits induced by dopamine administration with decreased glutathione. Free Radic Biol Med 24, 1149–1158.

    PubMed  CAS  Google Scholar 

  87. Amato, A., Connolly, C. N., Moss, S. J., and Smart, T. G. (1999) Modulation of neuronal and recombinant GABAA receptors by redox reagents. J Physiol 517 (Pt 1), 35–50.

    PubMed  CAS  Google Scholar 

  88. Joseph, S. K., Nakao, S. K., and Sukumvanich, S. (2006) Reactivity of free thiol groups in type-I inositol trisphosphate receptors. Biochem J 393, 575–582.

    PubMed  CAS  Google Scholar 

  89. Hidalgo, C., Bull, R., Behrens, M. I., and Donoso, P. (2004) Redox regulation of RyR-mediated Ca2+ release in muscle and neurons. Biol Res 37, 539–552.

    PubMed  Google Scholar 

  90. Sommer, D., Coleman, S., Swanson, S. A., and Stemmer, P. M. (2002) Differential susceptibilities of serine/threonine phosphatases to oxidative and nitrosative stress. Arch Biochem Biophys 404, 271–278.

    PubMed  CAS  Google Scholar 

  91. Campbell, D. L., Stamler, J. S., and Strauss, H. C. (1996) Redox modulation of L-type calcium channels in ferret ventricular myocytes. Dual mechanism regulation by nitric oxide and S-nitrosothiols. J Gen Physiol 108, 277–293.

    PubMed  CAS  Google Scholar 

  92. DiChiara, T. J. and Reinhart, P. H. (1997) Redox modulation of hslo Ca2+-activated K+ channels. J Neurosci 17, 4942–4955.

    PubMed  CAS  Google Scholar 

  93. Berman, S. B., Zigmond, M. J., and Hastings, T. G. (1996) Modification of dopamine transporter function: effect of reactive oxygen species and dopamine. J Neurochem 67, 593–600.

    PubMed  CAS  Google Scholar 

  94. Berman, S. B. and Hastings, T. G. (1997) Inhibition of glutamate transport in synaptosomes by dopamine oxidation and reactive oxygen species. J Neurochem 69, 1185–1195.

    PubMed  CAS  Google Scholar 

  95. Steullet, P., Lavoie, S., Kraftsik, R., Guidi, R., Gysin, R., Cuenod, M., and Do, K. Q. (2008) A glutathione deficit alters dopamine modulation of L-type calcium channels via D2 and ryanodine receptors in neurons. Free Radic Biol Med 44, 1042–1054.

    PubMed  CAS  Google Scholar 

  96. Tosic, M., Ott, J., Barral, S., Bovet, P., Deppen, P., Gheorghita, F., Matthey, M. L., Parnas, J., Preisig, M., Saraga, M., Solida, A., Timm, S., Wang, A. G., Werge, T., Cuenod, M., and Quang, D. K. (2006) Schizophrenia and oxidative stress: glutamate cysteine ligase modifier as a susceptibility gene. Am J Hum Genet 79, 586–592.

    PubMed  CAS  Google Scholar 

  97. Dalton, T. P., Chen, Y., Schneider, S. N., Nebert, D. W., and Shertzer, H. G. (2004) Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radic Biol Med 37, 1511–1526.

    PubMed  CAS  Google Scholar 

  98. Dalton, T. P., Dieter, M. Z., Yang, Y., Shertzer, H. G., and Nebert, D. W. (2000) Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem Biophys Res Commun 279, 324–329.

    PubMed  CAS  Google Scholar 

  99. Yang, Y., Dieter, M. Z., Chen, Y., Shertzer, H. G., Nebert, D. W., and Dalton, T. P. (2002) Initial characterization of the glutamate-cysteine ligase modifier subunit Gclm(−/−) knockout mouse. Novel model system for a severely compromised oxidative stress response. J Biol Chem 277, 49446–49452.

    PubMed  CAS  Google Scholar 

  100. Giordano, G., White, C. C., McConnachie, L. A., Fernandez, C., Kavanagh, T. J., and Costa, L. G. (2006) Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Mol Pharmacol 70, 2116–2126.

    PubMed  CAS  Google Scholar 

  101. Kishi, T., Ikeda, M., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Kawashima, K., Inada, T., Harano, M., Komiyama, T., Hori, T., Yamada, M., Iyo, M., Sora, I., Sekine, Y., Ozaki, N., Ujike, H., and Iwata, N. (2008) Glutamate cysteine ligase modifier (GCLM) subunit gene is not associated with methamphetamine-use disorder or schizophrenia in the Japanese population. Ann N Y Acad Sci 1139, 63–69.

    PubMed  CAS  Google Scholar 

  102. Butticaz, C., Werge, T., Beckmann, J. S., Cuenod, M., Do, K. Q., and Rivolta, C. (2009) Mutation screening of the glutamate cysteine ligase modifier (GCLM) gene in patients with schizophrenia. Psychiatr Genet 19, 201–208.

    PubMed  Google Scholar 

  103. Steullet, P., Cabungcal, J. H., Kulak, A., Kraftsik, R., Chen, Y., Dalton, T. P., Cuenod, M., and Do, Q. K. (2010) Redox dysregulation affects the ventral but not dorsal hippocampus: impairment of parvalbumin interneurons, gamma oscillations, and related behaviors. J Neurosci 30, 2547–2558.

    Google Scholar 

  104. Lavoie, S., Chen, Y., Dalton, T. P., Gysin, R., Cuenod, M., Steullet, P., and Do, K. Q. (2009) Curcumin, quercetin and tBHQ modulate glutathione levels in astrocytes and neurons: importance of the glutamate cysteine ligase modifier subunit. J Neurochem 108, 1410–1422.

    PubMed  CAS  Google Scholar 

  105. Cabungcal, J. H., Frank, A., Steullet, P., Kraftsik, R., Hornung, J. P., Chen, Y., Dalton, T. P., Cuenod, M., and Do, K. Q. (2008) Redox Dysregulation Impairs Normal Development of Parvalbumin-Positive Interneurons and Neuronal Circuitry of the Prefrontal Cortex in an Animal Model with Relevance to Schizophrenia http://www.sfn.org/am2008 – Neuroscience Meeting Planner. Society for Neuroscience, Washington, DC. Online.

  106. Behrens, M. M., Ali, S. S., Dao, D. N., Lucero, J., Shekhtman, G., Quick, K. L., and Dugan, L. L. (2007) Ketamine-induced loss of phenotype of fast-spiking interneurons is mediated by NADPH-oxidase. Science 318, 1645–1647.

    PubMed  CAS  Google Scholar 

  107. Baiano, M., David, A., Versace, A., Churchill, R., Balestrieri, M., and Brambilla, P. (2007) Anterior cingulate volumes in schizophrenia: a systematic review and a meta-analysis of MRI studies. Schizophr Res 93, 1–12.

    PubMed  CAS  Google Scholar 

  108. Goldman, M. B. and Mitchell, C. P. (2004) What is the functional significance of hippocampal pathology in schizophrenia? Schizophr Bull 30, 367–392.

    PubMed  Google Scholar 

  109. Smith, J., Ladi, E., Mayer-Proschel, M., and Noble, M. (2000) Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci USA 97, 10032–10037.

    PubMed  CAS  Google Scholar 

  110. Karoutzou, G., Emrich, H. M., and Dietrich, D. E. (2008) The myelin-pathogenesis puzzle in schizophrenia: a literature review. Mol Psychiatry 13, 245–260.

    PubMed  CAS  Google Scholar 

  111. Sohal, V. S., Zhang, F., Yizhar, O., and Deisseroth, K. (2009) Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702.

    PubMed  CAS  Google Scholar 

  112. Cho, R. Y., Konecky, R. O., and Carter, C. S. (2006) Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci USA 103, 19878–19883.

    PubMed  CAS  Google Scholar 

  113. Uhlhaas, P. J., Haenschel, C., Nikolic, D., and Singer, W. (2008) The role of oscillations and synchrony in cortical networks and their putative relevance for the pathophysiology of schizophrenia. Schizophr Bull 34, 927–943.

    PubMed  Google Scholar 

  114. Knyazeva, M.G., Jalili, M., Meuli, R., Hasler, M., De Feo, O., and Do, K.Q. (2008) Alpha rhythm and hypofrontality in schizophrenia. Acta Psychiatr Scand 118, 188–199.

    PubMed  CAS  Google Scholar 

  115. Bannerman, D. M., Rawlins, J. N., McHugh, S. B., Deacon, R. M., Yee, B. K., Bast, T., Zhang, W. N., Pothuizen, H. H., and Feldon, J. (2004) Regional dissociations within the hippocampus – memory and anxiety. Neurosci Biobehav Rev 28, 273–283.

    PubMed  CAS  Google Scholar 

  116. Bast, T., Zhang, W. N., and Feldon, J. (2001) The ventral hippocampus and fear conditioning in rats. Different anterograde amnesias of fear after tetrodotoxin inactivation and infusion of the GABA(A) agonist muscimol. Exp Brain Res 139, 39–52.

    PubMed  CAS  Google Scholar 

  117. Esclassan, F., Coutureau, E., Di, S. G., and Marchand, A. R. (2009) Differential contribution of dorsal and ventral hippocampus to trace and delay fear conditioning. Hippocampus 19, 33–44.

    PubMed  Google Scholar 

  118. Hunsaker, M. R. and Kesner, R. P. (2008) Dissociations across the dorsal-ventral axis of CA3 and CA1 for encoding and retrieval of contextual and auditory-cued fear. Neurobiol Learn Mem 89, 61–69.

    PubMed  Google Scholar 

  119. Bauer, D., Gupta, D., Harotunian, V., Meador-Woodruff, J. H., and McCullumsmith, R. E. (2008) Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia. Schizophr Res 104, 108–120.

    PubMed  Google Scholar 

  120. Nudmamud-Thanoi, S., Piyabhan, P., Harte, M. K., Cahir, M., and Reynolds, G. P. (2007) Deficits of neuronal glutamatergic markers in the caudate nucleus in schizophrenia. J Neural Transm Suppl 72, 281–285.

    PubMed  CAS  Google Scholar 

  121. Aoyama, K., Suh, S. W., Hamby, A. M., Liu, J., Chan, W. Y., Chen, Y., and Swanson, R. A. (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9, 119–126.

    PubMed  CAS  Google Scholar 

  122. Baker, D. A., McFarland, K., Lake, R. W., Shen, H., Tang, X. C., Toda, S., and Kalivas, P. W. (2003) Neuroadaptations in cysteine-glutamate exchange underlie cocaine relapse. Nat Neurosci 6, 743–749.

    PubMed  CAS  Google Scholar 

  123. Shih, A. Y., Erb, H., Sun, X., Toda, S., Kalivas, P. W., and Murphy, T. H. (2006) Cysteine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 26, 10514–10523.

    PubMed  CAS  Google Scholar 

  124. Ranjekar, P. K., Hinge, A., Hegde, M. V., Ghate, M., Kale, A., Sitasawad, S., Wagh, U. V., Debsikdar, V. B., and Mahadik, S. P. (2003) Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Psychiatry Res 121, 109–122.

    PubMed  CAS  Google Scholar 

  125. Campolo, J., Penco, S., Bianchi, E., Colombo, L., Parolini, M., Caruso, R., Sedda, V., Patrosso, M. C., Cighetti, G., Marocchi, A., and Parodi, O. (2007) Glutamate-cysteine ligase polymorphism, hypertension, and male sex are associated with cardiovascular events. Biochemical and genetic characterization of Italian subpopulation. Am Heart J 154, 1123–1129.

    PubMed  CAS  Google Scholar 

  126. Koide, S., Kugiyama, K., Sugiyama, S., Nakamura, S., Fukushima, H., Honda, O., Yoshimura, M., and Ogawa, H. (2003) Association of polymorphism in glutamate-cysteine ligase catalytic subunit gene with coronary vasomotor dysfunction and myocardial infarction. J Am Coll Cardiol 41, 539–545.

    PubMed  CAS  Google Scholar 

  127. Nakamura, S., Sugiyama, S., Fujioka, D., Kawabata, K., Ogawa, H., and Kugiyama, K. (2003) Polymorphism in glutamate-cysteine ligase modifier subunit gene is associated with impairment of nitric oxide-mediated coronary vasomotor function. Circulation 108, 1425–1427.

    PubMed  CAS  Google Scholar 

  128. Curkendall, S. M., Mo, J., Glasser, D. B., Rose, S. M., and Jones, J. K. (2004) Cardiovascular disease in patients with schizophrenia in Saskatchewan, Canada. J Clin Psychiatry 65, 715–720.

    PubMed  Google Scholar 

  129. Enger, C., Weatherby, L., Reynolds, R. F., Glasser, D. B., and Walker, A. M. (2004) Serious cardiovascular events and mortality among patients with schizophrenia. J Nerv Ment Dis 192, 19–27.

    PubMed  Google Scholar 

  130. Spelman, L. M., Walsh, P. I., Sharifi, N., Collins, P., and Thakore, J. H. (2007) Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia. Diabet Med 24, 481–485.

    PubMed  CAS  Google Scholar 

  131. Arana, C., Cutando, A., Ferrera, M. J., Gomez-Moreno, G., Worf, C. V., Bolanos, M. J., Escames, G., and Acuna-Castroviejo, D. (2006) Parameters of oxidative stress in saliva from diabetic and parenteral drug addict patients. J Oral Pathol Med 35, 554–559.

    PubMed  CAS  Google Scholar 

  132. Nwose, E. U., Jelinek, H. F., Richards, R. S., and Kerr, P. G. (2007) Erythrocyte oxidative stress in clinical management of diabetes and its cardiovascular complications. Br J Biomed Sci 64, 35–43.

    PubMed  CAS  Google Scholar 

  133. Dickinson, D., Gold, J. M., Dickerson, F. B., Medoff, D., and Dixon, L. B. (2008) Evidence of exacerbated cognitive deficits in schizophrenic patients with comorbid diabetes. Psychosomatics 49, 123–131.

    PubMed  Google Scholar 

  134. Fagiolini, A. and Goracci, A. (2009) The effects of undertreated chronic medical illnesses in patients with severe mental disorders. J Clin Psychiatry 70, Suppl 3, 22–29.

    PubMed  Google Scholar 

  135. Henderson, D. C. (2005) Schizophrenia and comorbid metabolic disorders. J Clin Psychiatry 66 Suppl 6, 11–20.

    PubMed  Google Scholar 

  136. Iacovides, A. and Siamouli, M. (2008) Comorbid mental and somatic disorders: an epidemiological perspective. Curr Opin Psychiatry 21, 417–421.

    PubMed  Google Scholar 

  137. Tietze, F. (1969) Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem 27, 502–522.

    PubMed  CAS  Google Scholar 

  138. Baker, M. A., Cerniglia, G. J., and Zaman, A. (1990) Microtiter plate assay for the measurement of glutathione and glutathione disulfide in large numbers of biological samples. Anal Biochem 190, 360–365.

    PubMed  CAS  Google Scholar 

  139. Keelan, J., Allen, N. J., Antcliffe, D., Pal, S., and Duchen, M. R. (2001) Quantitative imaging of glutathione in hippocampal neurons and glia in culture using monochlorobimane. J Neurosci Res 66, 873–884.

    PubMed  CAS  Google Scholar 

  140. Waak, J. and Dringen, R. (2006) Formation and rapid export of the monochlorobimane-glutathione conjugate in cultured rat astrocytes. Neurochem Res 31, 1409–1416.

    PubMed  CAS  Google Scholar 

  141. Sun, X., Erb, H., and Murphy, T. H. (2005) Coordinate regulation of glutathione metabolism in astrocytes by Nrf2. Biochem Biophys Res Commun 326, 371–377.

    PubMed  CAS  Google Scholar 

  142. Sun, X., Shih, A. Y., Johannssen, H. C., Erb, H., Li, P., and Murphy, T. H. (2006) Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood–brain interface. J Biol Chem 281, 17420–17431.

    PubMed  CAS  Google Scholar 

  143. Wallin, C., Weber, S. G., and Sandberg, M. (1999) Glutathione efflux induced by NMDA and kainate: implications in neurotoxicity? J Neurochem 73, 1566–1572.

    PubMed  CAS  Google Scholar 

  144. Zangerle, L., Cuenod, M., Winterhalter, K. H., and Do, K. Q. (1992) Screening of thiol compounds: depolarization-induced release of glutathione and cysteine from rat brain slices. J Neurochem 59, 181–189.

    PubMed  CAS  Google Scholar 

  145. Zhang, Z. J. and Reynolds, G. P. (2002) A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 55, 1–10.

    PubMed  Google Scholar 

  146. Laruelle, M., Abi-Dargham, A., van Dyck, C. H., Gil, R., D’Souza, C. D., Erdos, J., McCance, E., Rosenblatt, W., Fingado, C., Zoghbi, S. S., Baldwin, R. M., Seibyl, J. P., Krystal, J. H., Charney, D. S., and Innis, R. B. (1996) Single photon emission computerized tomography imaging of amphetamine- induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 93, 9235–9240.

    PubMed  CAS  Google Scholar 

  147. Hanlon, F. M., Weisend, M. P., Hamilton, D. A., Jones, A. P., Thoma, R. J., Huang, M., Martin, K., Yeo, R. A., Miller, G. A., and Canive, J. M. (2006) Impairment on the hippocampal-dependent virtual Morris water task in schizophrenia. Schizophr Res 87, 67–80.

    PubMed  Google Scholar 

  148. Cohen, B. D., Rosenbaum, G., Luby, E. D., and Gottlieb, J. S. (1962) Comparison of phencyclidine hydrochloride (Sernyl) with other drugs. Simulation of schizophrenic performance with phencyclidine hydrochloride (Sernyl), lysergic acid diethylamide (LSD-25), and amobarbital (Amytal) sodium; II. Symbolic and sequential thinking. Arch Gen Psychiatry 6, 395–401.

    PubMed  CAS  Google Scholar 

  149. Laruelle, M. (2000) The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 31, 371–384.

    PubMed  CAS  Google Scholar 

  150. RScholten, M. R., van, H. J., Aleman, A., and Kahn, R. S. (2006) Behavioral inhibition system (BIS), behavioral activation system (BAS) and schizophrenia: relationship with psychopathology and physiology. J Psychiatr Res 40, 638–645.

    Google Scholar 

Download references

Acknowledgments

We would like to acknowledge all collaborators who contributed significantly to the development and study of some of the models described in this review. This includes in particular Beatrix Benz, Vincent Castagné, Ying Chen, Adeline Cottier, Timothy P. Dalton, Fulvia Gheorghita, Gilbert Grima, Jean-Pierre Hornung, Rudolf Kraftsik, Suzie Lavoie, Delphine Preissmann. We are also grateful to Pierre Magistretti for his constant encouragement and Paul Herrling for his support in the initial phase of the project. Work supported by the Swiss Research Foundation (grants nos. 31-55924.98 and 31-116689 to K.Q. Do; grant no. 3100A0–105765 to F. Schenk) and the foundation “Loterie Romande.”

Author information

Authors and Affiliations

  1. Department of Psychiatry, Center for Psychiatric Neuroscience, Centre Hospitalier Universitaire Vaudois, Prilly-Lausanne, Switzerland

    Pascal Steullet

  2. Department of Psychiatry, University of Lausanne, Lausanne, Switzerland

    Jan-Harry Cabungcal, Anita Kulak, Michel Cuenod, Françoise Schenk & Kim Q. Do

Authors
  1. Pascal Steullet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jan-Harry Cabungcal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anita Kulak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel Cuenod
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Françoise Schenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kim Q. Do
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pascal Steullet .

Editor information

Editors and Affiliations

  1. School of Medicine, Depts. of Anatomy & Neurobiology, University of Maryland, Penn St. 20, Baltimore, 21201, Maryland, USA

    Patricio O'Donnell

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Steullet, P., Cabungcal, JH., Kulak, A., Cuenod, M., Schenk, F., Do, K.Q. (2011). Glutathione Deficit and Redox Dysregulation in Animal Models of Schizophrenia. In: O'Donnell, P. (eds) Animal Models of Schizophrenia and Related Disorders. Neuromethods, vol 59. Humana Press. https://doi.org/10.1007/978-1-61779-157-4_7

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-157-4_7

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-156-7

  • Online ISBN: 978-1-61779-157-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation