Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia

Boks, Marco P.; Rietkerk, Thomas; Beek, Madelien Hermina van de; Sommer, Iris E.; Koning, Tom J. de; Kahn, René S.

doi:10.1016/j.euroneuro.2006.12.003

Cited by 71 publications

(59 citation statements)

References 53 publications

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“…DAAO is relevant in NMDA receptor signaling [96]. DAAO knockout mice have increased D-serine levels in the cerebellum and the medulla but no change in D-serine levels in the forebrain [96]. Morphine administration produced a dose-dependent and transient elevation of mRNA expression of DAAO in all the brain areas which suggested an interaction between the mRNA expression of D-serine-related enzymes and opioid receptor activation [97].…”

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

“…In this context, Korostishevsky et al showed increased G72 expression in the dorsolateral prefrontal cortex of schizophrenia patients as compared to healthy controls [99,96].…”

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

“…DAAO oxidizes D-amino acids, especially proline, methionine and alanine but also D-amino acids like D-glutamate and Daspartate, which are poorer substrates for DAAO [96]. DAAO is relevant in NMDA receptor signaling [96]. DAAO knockout mice have increased D-serine levels in the cerebellum and the medulla but no change in D-serine levels in the forebrain [96].…”

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

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Molecular Mechanisms of Schizophrenia

Lang¹,

Puls²,

Müller³

et al. 2007

Cell Physiol Biochem

250

165

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Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.

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Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

“…In this context, Korostishevsky et al showed increased G72 expression in the dorsolateral prefrontal cortex of schizophrenia patients as compared to healthy controls [99,96].…”

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

Section: The Glutamatergic Hypothesis Of Schizophreniamentioning

confidence: 99%

See 2 more Smart Citations

Molecular Mechanisms of Schizophrenia

Lang¹,

Puls²,

Müller³

et al. 2007

Cell Physiol Biochem

250

165

View full text Add to dashboard Cite

show abstract

“…4 6) With regard to schizophrenia, one of the severe psychiatric diseases, the``glutamate hypothesis'' has recently been postulated; this hypothesis suggests that the etiology of schizophrenia may be associated with the hypofunction of the NMDA receptor. 7,8) There have been reports stating that DAAO is one of the products of a susceptibility gene for schizophrenia 9) and that the activity of brain DAAO, which degrades D-serine, was found to be increased in the post-mortem brain tissue of patients with schizophrenia. 10) In addition, we previously reported that the serum D-serine concentration was signiˆcantly reduced in patients with schizophrenia.…”

mentioning

confidence: 99%

Inhibition of D-Amino Acid Oxidase Activity by Antipsychotic Drugs Evaluated by a Fluorometric Assay Using D-Kynurenine as Substrate

et al. 2011

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A facile ‰uorometric assay using D-kynurenine as a substrate was utilized for evaluating the inhibition of D-amino acid oxidase (DAAO), which is one of the products of a susceptibility gene for schizophrenia, by commercial antipsychotic drugs, namely, chlorpromazine (CPZ), carbamazepine, sulpiride, quetiapine, and imipramine. CPZ inhibited DAAO (65.8±13.2 mM, n＝3) as reported previously, and other drugs also inhibited DAAO activity. Among these, quetiapine had the smallest IC 50 value (19.5±2.60 mM, n＝3). The proposed assay can be useful for the evaluation or screening of DAAO-inhibitory drugs.

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Add-on Treatment of Benzoate for Schizophrenia

et al. 2013

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In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURESThe primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. CONCLUSIONS AND RELEVANCEBenzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT 00960219

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Reviewing the role of the genes G72 and DAAO in glutamate neurotransmission in schizophrenia

Cited by 71 publications

References 53 publications

Molecular Mechanisms of Schizophrenia

Molecular Mechanisms of Schizophrenia

Inhibition of D-Amino Acid Oxidase Activity by Antipsychotic Drugs Evaluated by a Fluorometric Assay Using D-Kynurenine as Substrate

Add-on Treatment of Benzoate for Schizophrenia

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