A single-base-pair substitution abolishes d-amino-acid oxidase activity in the mouse

Sato, Masato; Konno, Ryuichi; Nihio, Masahiro; Niwa, Akira; Yasumura, Yosihiro; Enami, Jumpei

doi:10.1016/0925-4439(92)90107-x

Cited by 47 publications

(40 citation statements)

References 24 publications

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“…The Dao1 G181R mice were obtained from the Konno laboratory that initially identified this spontaneous missense mutation (glycine to arginine at amino acid 181) in the Dao1 gene of the ddY strain, resulting in a complete loss of DAO activity (Konno and Yasumura 1983;Sasaki et al 1992). The Dao1 G181R mutation was transferred onto a C57BL/6J genetic background using a marker-assisted speed congenic strategy (Wong 2002).…”

Section: Subjectsmentioning

confidence: 99%

“…An inverse correlation between the brain distribution of DAO and Dserine evinces the efficacy of this enzyme, with the most abundant DAO expression located in the D-serine-sparse hindbrain and cerebellum (Schell et al 1995;Moreno et al 1999). To study the effects of limiting DAO function, we tested a line of mice carrying a single point mutation (G181R) that results in a complete lack of DAO activity and consequently augmented D-serine in serum and brain (Sasaki et al 1992;Hashimoto et al 1993). These mice have previously been shown to exhibit an in vitro increase in NMDARmediated excitatory postsynaptic currents in dorsal horn neurons of the spinal cord and an in vivo elevation of cGMP that is indicative of augmented NMDAR activity (Wake et al 2001;Almond et al 2006).…”

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confidence: 99%

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Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

Labrie¹,

Duffy²,

Wang³

et al. 2008

Learn. Mem.

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Activation of the N-methyl-D-aspartate receptor (NMDAR) glycine site has been shown to accelerate adaptive forms of learning that may benefit psychopathologies involving cognitive and perseverative disturbances. In this study, the effects of increasing the brain levels of the endogenous NMDAR glycine site agonist D-serine, through the genetic inactivation of its catabolic enzyme D-amino acid oxidase (DAO), were examined in behavioral tests of learning and memory. In the Morris water maze task (MWM), mice carrying the hypofunctional Dao1 G181R mutation demonstrated normal acquisition of a single platform location but had substantially improved memory for a new target location in the subsequent reversal phase. Furthermore, Dao1 G181R mutant animals exhibited an increased rate of extinction in the MWM that was similarly observed following pharmacological administration of D-serine (600 mg/kg) in wild-type C57BL/6J mice. In contextual and cued fear conditioning, no alterations were found in initial associative memory recall; however, extinction of the contextual fear memory was facilitated in mutant animals. Thus, an augmented level of D-serine resulting from reduced DAO activity promotes adaptive learning in response to changing conditions. The NMDAR glycine site and DAO may be promising therapeutic targets to improve cognitive flexibility and inhibitory learning in psychiatric disorders such as schizophrenia and anxiety syndromes.

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Section: Subjectsmentioning

confidence: 99%

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confidence: 99%

Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

Labrie¹,

Duffy²,

Wang³

et al. 2008

Learn. Mem.

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“…32) However, cloning and sequencing indicated the presence of a missense mutation (Gly181Arg) in the middle of the cDNA encoding DAO in the ddY/DAO Ϫ mice. 33) This mutation caused a complete loss of DAO activity both in the kidney and in the brain. Since the ddY/DAO Ϫ mice accumulate a large amount of D-amino acids, these animals are useful for the development and evaluation of the analytical methods of D-amino acids.…”

Section: A Mutant Mouse Strain Lacking Dao Ac-tivitymentioning

confidence: 99%

Sensitive Determination of D-Amino Acids in Mammals and the Effect of D-Amino-Acid Oxidase Activity on Their Amounts

Hamase

Konno

Morikawa

et al. 2005

Biological & Pharmaceutical Bulletin

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“…ddY/ DAO − mice, found in outbred ddY mice (12), lack DAO activity because of a natural point mutation (G181R) (13) and show abnormal locomotor behavior related to enhanced NMDAR function (14). Because hypofunction of the NMDAR and genetic association of DAO have been implicated in schizophrenia, most studies using ddY/DAO − mice have focused on a therapeutic approach to schizophrenia through D-serine increase.…”

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confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

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

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/ familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.excitotoxicity | motor neuron disease | neurodegeneration | enzyme histochemistry | 2D-HPLC A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1, 2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated.The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca ...

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A single-base-pair substitution abolishes d-amino-acid oxidase activity in the mouse

Cited by 47 publications

References 24 publications

Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

Genetic inactivation of D-amino acid oxidase enhances extinction and reversal learning in mice

Sensitive Determination of D-Amino Acids in Mammals and the Effect of D-Amino-Acid Oxidase Activity on Their Amounts

d -Amino acid oxidase controls motoneuron degeneration through d -serine

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