Schizophrenia and Oxidative Stress: Glutamate Cysteine Ligase Modifier as a Susceptibility Gene

Toŝić, Mirjana; Ott, Jürg; Barral, Sandra; Bovet, Pascal; Deppen, Patricia; Gheorghita, F.; Matthey, Marie-Louise; Parnas, Josef; Preisig, Martin; Saraga, Michaël; Solida, Alessandra; Timm, Sally; Wang, August G.; Werge, Thomas; Cuénod, Michel; Q., Kim

doi:10.1086/507566

Cited by 208 publications

(173 citation statements)

References 39 publications

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“…Considering that brain GSH deficiency in schizophrenia seems to be associated with a defect in the key synthesizing enzyme glutamyl-cysteine ligase (Gysin et al, 2007;Tosic et al, 2006), that conjugates cysteine to glutamate in the first step of GSH synthesis, a cysteine precursor might not represent the best substance to use to increase GSH levels. Substances that bypass this enzyme would represent better choices; however, raising new challenges for their efficient delivery across the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence indicates that there is a defect in GSH synthesis at the level of the key synthesizing enzyme, glutamate cysteine ligase. Polymorphisms in the gene of the modifier subunit of this enzyme as well as decreased expression of this gene have been associated with schizophrenia (Do et al, in press;Tosic et al, 2006;Gysin et al, 2007). GSH is a major antioxidant and redox regulator that protects cells against oxidative stress (Meister and Anderson, 1983).…”

Section: Introductionmentioning

confidence: 99%

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Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Lavoie

Murray

Deppen

et al. 2007

Neuropsychopharmacol

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In schizophrenia patients, glutathione dysregulation at the gene, protein and functional levels, leads to N-methyl-D-aspartate (NMDA) receptor hypofunction. These patients also exhibit deficits in auditory sensory processing that manifests as impaired mismatch negativity (MMN), which is an auditory evoked potential (AEP) component related to NMDA receptor function. N-acetyl-cysteine (NAC), a glutathione precursor, was administered to patients to determine whether increased levels of brain glutathione would improve MMN and by extension NMDA function. A randomized, double-blind, cross-over protocol was conducted, entailing the administration of NAC (2g/day) for 60 days and then placebo for another 60 days (or vice versa). 128-channel AEPs were recorded during a frequency oddball discrimination task at protocol onset, at the point of cross-over, and at the end of the study. At the onset of the protocol, the MMN of patients was significantly impaired compared to sex-and age-matched healthy controls (p ¼ 0.003), without any evidence of concomitant P300 component deficits. Treatment with NAC significantly improved MMN generation compared with placebo (p ¼ 0.025) without any measurable effects on the P300 component. MMN improvement was observed in the absence of robust changes in assessments of clinical severity, though the latter was observed in a larger and more prolonged clinical study. This pattern suggests that MMN enhancement may precede changes to indices of clinical severity, highlighting the possible utility AEPs as a biomarker of treatment efficacy. The improvement of this functional marker may indicate an important pathway towards new therapeutic strategies that target glutathione dysregulation in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Lavoie

Murray

Deppen

et al. 2007

Neuropsychopharmacol

Self Cite

325

221

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“…Glutathione (GSH), responsible for detoxification of reactive oxygen and other radical species, is consistently decreased in cerebrospinal fluid of drug-naïve schizophrenia patients (Do et al, 2000), as well as in postmortem tissue (Yao et al, 2006). Polymorphisms in genes coding for enzymes that participate in GSH synthesis have been linked to schizophrenia risk (Tosic et al, 2006;Gysin et al, 2007), and acute frontal-brain GSH depletion in adult rodents was recently shown to produce disruptions in short-term memory, supporting the link between depletion of brain GSH levels and cognitive impairments that occur in schizophrenia (Pileblad et al, 1989;Jacobsen et al, 2005;Dean et al, 2009). Moreover, acute GSH depletion potentiates the release of dopamine produced by amphetamine in striatum and potentiates the behavioral effects of NMDA-R antagonists as a well as those of amphetamine (Jacobsen et al, 2005).…”

Section: The Role Of Superoxide In the Persistent Effects Of Nmda-r Amentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

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“…14,18 We thus proposed that a redox dysregulation represents one hub on which converge various causal genetic and environmental risk factors during neurodevelopment, leading to structural and functional connectivity impairments. The genetic vulnerability factors involve either redox regulation genes directly affecting GSH metabolism, [19][20][21][22] or genes that indirectly lead to oxidative stress, including DISC1, PROD, G72, NRG and DTNBP1. [23][24][25][26][27] Environmental factors known to favor major psychiatric disorders also generate reactive oxygen species (ROS), which, if the redox regulation is impaired, will perturb the developing nervous system.…”

Section: Introductionmentioning

confidence: 99%

“…As a consequence, two key systems essential for cognitive and affective functioning will be particularly affected: local microcircuits and long-range connections. More specifically, polymorphisms in the genes coding for the catalytic (GCLC) 20 and modifier (GCLM) 22 subunits of the glutamatecysteine ligase (GCL), the rate-limiting enzyme for GSH synthesis, are associated with schizophrenia in case-control studies. The GAG trinucleotide repeat polymorphisms of GCLC, which are more frequent in patients ('GAG high-risk' genotypes), 20 are associated with changes in plasma thiol levels.…”

Section: Introductionmentioning

confidence: 99%

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

et al. 2014

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Schizophrenia pathophysiology implies both abnormal redox control and dysconnectivity of the prefrontal cortex, partly related to oligodendrocyte and myelin impairments. As oligodendrocytes are highly vulnerable to altered redox state, we investigated the interplay between glutathione and myelin. In control subjects, multimodal brain imaging revealed a positive association between medial prefrontal glutathione levels and both white matter integrity and resting-state functional connectivity along the cingulum bundle. In early psychosis patients, only white matter integrity was correlated with glutathione levels. On the other side, in the prefrontal cortex of peripubertal mice with genetically impaired glutathione synthesis, mature oligodendrocyte numbers, as well as myelin markers, were decreased. At the molecular levels, under glutathione-deficit conditions induced by short hairpin RNA targeting the key glutathione synthesis enzyme, oligodendrocyte progenitors showed a decreased proliferation mediated by an upregulation of Fyn kinase activity, reversed by either the antioxidant N-acetylcysteine or Fyn kinase inhibitors. In addition, oligodendrocyte maturation was impaired. Interestingly, the regulation of Fyn mRNA and protein expression was also impaired in fibroblasts of patients deficient in glutathione synthesis. Thus, glutathione and redox regulation have a critical role in myelination processes and white matter maturation in the prefrontal cortex of rodent and human, a mechanism potentially disrupted in schizophrenia.

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Schizophrenia and Oxidative Stress: Glutamate Cysteine Ligase Modifier as a Susceptibility Gene

Cited by 208 publications

References 39 publications

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Glutathione Precursor, N-Acetyl-Cysteine, Improves Mismatch Negativity in Schizophrenia Patients

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients

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