Mice lacking d-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801

doi:10.1016/j.brainres.2004.11.031

Brain Research

Volume 1033, Issue 2, 8 February 2005, Pages 210-215

https://doi.org/10.1016/j.brainres.2004.11.031 Get rights and content

Abstract

The behavioral effects produced by MK-801 (0.4 mg/kg) were compared in mutant DAO−/− mice lacking d-amino acid oxidase activity and normal DAO+/+ mice. Mutant mice display marked diminution of stereotypy and ataxia induced by MK-801 compared to normal mice. Because the d-serine level in the brain of mutant mice is significantly higher than that of normal mice, the elevated d-serine in the brain of mutant mice could antagonize MK-801-induced stereotypy and ataxia.

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Acknowledgments

This study was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Asahi Glass Foundation.

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Citation Excerpt :
Consistent with the NMDA receptor hypofunction hypothesis in schizophrenia, an increase in DAO enzyme activity and gene expression has been reported in postmortem brain tissue of patients with schizophrenia (Bendikov et al., 2007). Mice lacking DAO (DAO−/−) exhibit increased occupancy of the NMDA receptor–associated glycine site, with a consequent increase in NMDA receptor signaling but also display a reduced behavioral sensitivity to acute administration of the NMDA antagonists MK-801 (Hashimoto, Yoshikawa, Niwa, & Konno, 2005) and phencyclidine (Almond et al., 2006). Behavioral analyses of these mutant mice revealed reduced exploration in a novel environment relative to their wild-type counterparts (Almond et al., 2006; Zhang et al., 2011), altered anxiety (Labrie, Clapcote, & Roder, 2009; Zhang et al., 2011), enhanced extinction of contextual fear memory and reversal learning abilities (Labrie, Duffy, et al., 2009), and both enhanced PPI responses (Zhang et al., 2011) and no effects in this test (Almond et al., 2006).
Genetic association approaches and the more recent contributions from genome-wide association studies have identified a number of risk genes for schizophrenia that potentially contribute to pathology in this neurodevelopmental disorder. The development of mutant mouse models of candidate risk genes and the examination of mutant mouse phenotypes allow direct associations to be made between these genes, specific pathological processes, and behavioral phenotypes, and hence, shed light on genetic contributions to the pathophysiology of schizophrenia. The present review examines some of the approaches adopted in the engineering and phenotypic assessment of mutant models. The most commonly used genetic mouse models in this preclinical field and the principal findings that have emerged from these studies are summarized. Finally, the key challenges and methodological issues associated with replicating gene mutations of identified schizophrenia risk genes in rodents are discussed.
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As animal models of psychotic illness become more refined, mutant mouse models have become increasingly prominent through their ability to inform on the structural, cellular and behavioural roles of genes associated with risk for psychosis via the phenotypic consequences of disruption of those genes. This review will consider recent advances in the field whereby mutant mouse models seek to reflect increasing knowledge of psychotic illness, focusing on four main themes. Firstly, recent GWAS and rare variant analyses have identified that disease-associated targets have not been previously implicated, thereby representing novel biological pathways in the illness, and this has implications for the modelling field. Secondly, the psychosis is disrespectful to conventional diagnostic boundaries, both clinically and in terms of pathobiology: it extends beyond schizophrenia to include several diagnostic categories and may be best captured in terms of psychopathological dimensions rather than/additional to such categories. Thirdly, a given risk gene (G) does not operate in isolation but, rather, appears to participate in complex interactions with environmental (E) risk factors, i.e. G × E interactions. Lastly, a given risk gene is likely to participate in complex, epistatic interactions with other risk genes, i.e. G × G interactions. Such studies constitute important steps in closing the translational gap between mutant mouse models and the clinical reality of psychotic illness.
D-aspartate dysregulation in Ddo<sup>-/-</sup> mice modulates phencyclidine-induced gene expression changes of postsynaptic density molecules in cortex and striatum
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N-methyl-D-aspartate receptor (NMDAR) hypofunction has been considered a key alteration in schizophrenia pathophysiology. Thus, several strategies aimed at enhancing glutamatergic transmission, included the introduction in therapy of D-amino acids, such as D-serine and D-cycloserine augmentation, have been proposed to counteract difficult-to-treat symptoms or treatment-resistant forms of schizophrenia. Another D-amino acid, D-aspartate, has recently gained increasing interest for its role in NMDAR activation and has been found reduced in post-mortem cortex of schizophrenia patients. NMDAR is the core of the postsynaptic density (PSD), a postsynaptic site involved in glutamate signaling and responsive to antipsychotic treatment.
In this study, we investigated striatal and cortical gene expression of key PSD transcripts (i.e. Homer1a, Homer1b/c, and PSD-95) in mice with persistently elevated brain D-aspartate-levels, i.e. the D-aspartate-oxidase knockout mice (Ddo^−/−). These animal models were analyzed both in naive condition and after phencyclidine (PCP) treatment. Naive Ddo^−/− mice showed decreased Homer1a expression in the prefrontal cortex, increased Homer1b/c expression in the striatum, and decreased PSD-95 expression in the striatum and in the cortex. Acute PCP treatment restored, and even potentiated, Homer1a expression in the prefrontal cortex of mutant mice, while it had limited effects on the other genes. These results suggest that persistently elevated D-aspartate, by enhancing NMDA transmission, may cause complex adaptive mechanisms affecting Homer1a, which in turn may explain the recently demonstrated protective effects of this D-amino acid against PCP-induced behavioral alterations, such as ataxic behavior.
Screening of central functions of amino acids and their metabolites for sedative and hypnotic effects using chick models
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The chick has a practical advantage in the screening process in that chicks require only small quantities of drugs. The chick separation stress paradigm has traditionally been recognized as a valid form of anxiolytic screening. Further, chick behavior involving standing motionless with eyes closed or sitting motionless with head drooped is nearly always associated with electrophysiological sleep.
When centrally administered, some DNA-encoded L-α-amino acids, as well as some DNA-non-encoded amino acids, such as metabolites of L-α-amino acids, D-amino acid and β-amino acid, have shown sedative and/or hypnotic effects in chicks. The effects of some of these amino acids have subsequently been confirmed in humans.
In conclusion, the chick model is convenient and useful for screening central functions of amino acids and their metabolites for hypnosis and sedation.
Timing-dependent reduction in ethanol sedation and drinking preference by NMDA receptor co-agonist d-serine
2012, Alcohol
NMDA receptors become a major contributor to acute ethanol intoxication effects at high concentrations as ethanol binds to a unique site on the receptor and inhibits glutamatergic activity in multiple brain areas. Although a convincing body of literature exists on the ability of NMDA receptor antagonists to mimic and worsen cellular and behavioral ethanol effects, receptor agonists have been less well-studied. In addition to a primary agonist site for glutamate, the NMDA receptor contains a separate co-agonist site that responds to endogenous amino acids glycine and d-serine. d-serine is both selective for this co-agonist site and potent in boosting NMDA dependent activity even after systemic administration. In this study, we hypothesized that exogenous d-serine might ameliorate some acute ethanol behaviors by opposing NMDA receptor inhibition. We injected adult male C57 mice with a high concentration of d-serine at various time windows relative to ethanol administration and monitored sedation, motor coordination and voluntary ethanol drinking. d-serine (2.7 g/kg, ip) prolonged latency to a loss of righting reflex (LoRR) and shortened LoRR duration when given 15 min before ethanol (3 g/kg) but not when it was injected with or shortly after ethanol. Blood samples taken at sedative recovery and at fixed time intervals revealed no effect of d-serine on ethanol concentration but an ethanol-induced decrease in l-serine and glycine content was prevented by acute d-serine pre-administration. d-serine had no effect on ethanol-induced (2 g/kg) rotarod deficits in young adult animals but independently and interactively degraded motor performance in a subset of older mice. Finally, a week-long series of daily ip injections resulted in a 50% decrease in free choice ethanol preference for d-serine treated animals compared to saline-injected controls in a two-bottle choice experiment.
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Citation Excerpt :
In comparison to wild-type animals, mice carrying the DAOG181R mutation do not display differences in social interactions, latent inhibition, startle reactivity, learning of a single spatial location and object recognition memory (Labrie et al., 2010, 2009b; Zhang et al., 2010; Almond et al., 2006). However, the DAOG181R mutation was shown to attenuate hyperactivity, stereotypy and ataxia induced by MK-801 (Almond et al., 2006; Hashimoto et al., 2005a) or methamphetamine (Hashimoto et al., 2008a). The efficacy of DAO inactivation in decreasing behavioral abnormalities induced by diminished NMDAR function has been tested by combining the Grin1D481N and DAOG181R mutation (Labrie et al., 2010).
The glutamate neurotransmitter system is one of the major candidate pathways for the pathophysiology of schizophrenia, and increased understanding of the pharmacology, molecular biology and biochemistry of this system may lead to novel treatments. Glutamatergic hypofunction, particularly at the NMDA receptor, has been hypothesized to underlie many of the symptoms of schizophrenia, including psychosis, negative symptoms and cognitive impairment. This review will focus on d-serine, a co-agonist at the NMDA receptor that in combination with glutamate, is required for full activation of this ion channel receptor. Evidence implicating d-serine, NMDA receptors and related molecules, such as d-amino acid oxidase (DAO), G72 and serine racemase (SRR), in the etiology or pathophysiology of schizophrenia is discussed, including knowledge gained from mouse models with altered d-serine pathway genes and from preliminary clinical trials with d-serine itself or compounds modulating the d-serine pathway. Abnormalities in d-serine availability may underlie glutamatergic dysfunction in schizophrenia, and the development of new treatments acting through the d-serine pathway may significantly improve outcomes for many schizophrenia patients.
This article is part of a Special Issue entitled ‘Schizophrenia’.

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Short communicationMice lacking d-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801

Abstract

Section snippets

Acknowledgments

Neuropharmacology

Eur. J. Pharmacol.

Lancet

Prog. Neurobiol.

Neurosci. Lett.

Neuroscience

Brain Res.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Cell

Biophys. J.

Biochim. Biophys. Acta

Brain Res.

Biol. Psychiatry

Neurosci. Lett.

Mol. Brain Res.

Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia

Proc. Natl. Acad. Sci. U. S. A.

A “glutamatergic hypothesis” of schizophrenia. Rationale for pharmacotherapy with glycine

Clin. Neuropharmacol.

Molecular cloning and sequence of cDNAs encoding porcine kidney d-amino acid oxidase

Biochemistry

Short communication
Mice lacking d-amino acid oxidase activity display marked attenuation of stereotypy and ataxia induced by MK-801