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Redox Dysregulation in Schizophrenia: Genetic Susceptibility and Pathophysiological Mechanisms

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

Schizophrenia is a severe, frequent, chronic and complex disease implying an interplay of genetic, environmental and developmental vulnerability factors. Its physiopathology involves an impairment of neural connectivity both at the functional and structural levels, and various transmitter systems. Increasing evidence points to the involvement in the disease of oxidative stress and redox imbalance, although their origin is still elusive. Glutathione plays a major role as a redox regulator and is required as antioxidant for cellular protection against oxidative damage. It is synthesized by the rate-limiting enzyme glutamate-cysteine ligase (GCL).

The evidence for its involvement in schizophrenia is summarized below.

  • Glutathione synthesis is impaired in patients at the level of the GCL enzyme, as measured in fibroblasts. In addition, genetic analysis showed an association between schizophrenia and the two GCL subunits. These findings are consistent with low brain and cerebrospinal fluid (CSF) glutathione levels.

  • It is proposed that a brain glutathione deficit leads to the depression of N-methyl-D-aspartate (NMDA) responses and affect synaptic contacts in catecholamine innervated regions.

  • Experimental pharmacological in vitro models in which glutathione is decreased reveal a hypofunction of NMDA receptors. In vivo developmental models show a reduction of dendritic spine density and of γ-aminobutyric acid (GABA)-parvalbumin immunoreactive interneurones in prefrontal cortex, as well as memory and sensory integration impairments. These anomalies are similar to that observed in schizophrenia.

  • In a clinical trial, oral administration of N-acetyl-cysteine, a glutathione precursor, improves clinical symptoms and mismatch negativity.

  • The data are compatible with the dopamine, glutamate and neurodevelopmental hypotheses as well as with schizophrenia comorbidities, including cardiovascular diseases, diabetes, viral infections, neonatal complications and hyperhomocysteinemia.

A redox/antioxidant dysregulation due to an impairment of glutathione synthesis of genetic origin is a vulnerability factor for schizophrenia.

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Abbreviations

BSO:

Buthionine Sulfoximine

CAT:

Catalase

CSF:

Cerebrospinal Fluid

DA:

Dopamine

GAD-67:

Glutamate Decarboxylase 67

GCL:

Glutamate-Cysteine Ligase

GCLC:

Glutamate-Cysteine Ligase Catalytic Subunit

GCLM:

Glutamate-Cysteine Ligase Modifier Subunit

GGT:

γ-Glutamyl Transpeptidase

GPX:

Glutathione Peroxidase

GSH:

Glutathione

GSS:

Glutathione Synthetase

GSSG:

Oxidized Form of Glutathione

GSTM:

Glutamyl-S-Transferase

LPS:

Lipopolysaccharide

MMN:

Mismatch Negativity

NAC:

N-Acetyl Cysteine

NEG:

Negative

ODS:

“Osteogenic Disorder Shionogi”

Oligo:

Oligodendrocytes

PFC:

Prefrontal Cortex

POS:

Positive

PV:

Parvalbumin

RNS:

Reactive Nitrogen Species

ROS:

Reactive Oxygen Species

SOD:

Superoxide Dismutase

t-BHQ:

tert-Buthylhydroquinone

TNR:

Trinucleotide Repeat

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Acknowledgments

We would like to thank all the patients and controls subjects who participated in the studies. Our thanks also go to the following collaborators who were involved in the project: O. Boulat, V. Castagne, P. Deppen, F. Gheorghita, G. Grima, J. P. Hornung, M. Knyazeva, M. L. Matthey, R. Meuli, M. Murray, M. Preisig, V. Ruiz, M. Saraga, F. Schenk, A. Solida, J. Sandell and M. Tosic. We are grateful to Prof P. Magistretti for his constant support. We also thank the technical collaborators N. Ballanfat, B. Benz, M. Blanc, V. Perroud and S. Reymond. This work has been supported by the Swiss National Foundation, Novartis Research Foundation, the “Loterie Romande,” NARSAD, Foundation Pro Scientia et Arte and the Foundation Alamaya for research on schizophrenia.

Authors
  1. K. Q. Do
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  2. P. Bovet
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  3. J. H. Cabungcal
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  4. P. Conus
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  5. R. Gysin
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  6. S. Lavoie
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  7. P. Steullet
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  8. M. Cuenod
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, Orangeburg, New York, USA

    Abel Lajtha (Director) (Director)

  2. Program in Cognitive Neuroscience and Schizophrenia, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York, 10962, USA

    Daniel Javitt (Director) (Director)

  3. Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, New York, 10962, USA

    Joshua Kantrowitz

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Do, K.Q. et al. (2009). Redox Dysregulation in Schizophrenia: Genetic Susceptibility and Pathophysiological Mechanisms. In: Lajtha, A., Javitt, D., Kantrowitz, J. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30410-6_8

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