Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia

Almond, Sarah; Fradley, Rosa; Armstrong, E.J.; Heavens, R.B.; Rutter, A. Richard; Newman, Robert J.; Chiu, Chi-Sung; Konno, Ryuichi; Hutson, Peter H.; Brandon, Nicholas J.

doi:10.1016/j.mcn.2006.05.003

Cited by 97 publications

(66 citation statements)

References 54 publications

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“…Conversely, no alterations in cerebellar cGMP levels were found in Ddo Ϫ/Ϫ mice. Notably, also in ddY/DAO Ϫ mutants, characterized to have higher levels of the endogenous coagonist D-serine, basal in vivo NMDAR activity did not differ from their controls (Almond et al, 2006). To explain this paradox, in line with Almond et al (2006), we suggest that the absence of DDO since early postnatal developmental stages might result in an overall desensitization of the NMDARnitric-oxide-mediated response.…”

Section: Discussionmentioning

confidence: 78%

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

et al. 2008

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IntroductionSchizophrenia (SCZ) is a severe mental disorder afflicting ϳ1% of the population worldwide. Despite decades of intensive research, the precise etiology of this devastating mental illness remains, so far, an unresolved puzzle (Sawa and Snyder, 2002). It has been proposed that dysfunction of dopaminergic neurotransmission occurs in SCZ patients (Snyder, 1976); however, a large body of evidence recently proposed that abnormal serotonergic and glutamatergic neurotransmission might also be implicated in the pathophysiological processes leading to the development of schizophrenia (González-Maeso et al., 2008). Compelling evidence from genetic, brain imaging, and clinical studies strongly suggests that psychotic symptoms might be associated with a persistent hypoglutamatergic transmission involving reduced NMDA receptor (NMDAR) activation (Tsai and Coyle, 2002). This hypothesis is mainly based on two fundamental observations: first, administration to healthy subjects of noncompetitive NMDAR antagonists, such as phencyclidine (PCP) or ketamine, results in severe mental symptoms resembling those of schizophrenic patients; second, administration of PCP to psychotic patients exacerbates positive and negative symptoms and worsens their cognitive functions (Javitt and Zukin, 1991;Olney and Farber, 1995). Together, these findings suggest that interventions able to enhance NMDAR transmission might be beneficial for the treatment of SCZ (Kristiansen et al., 2007). In particular, administration of D-serine to clozapine-treated patients ameliorates their positive, negative, and cognitive deficits (Tsai et al., 1999).D-Serine is a D-amino acid occurring in the mammalian forebrain throughout postnatal lifetime (Schell et al., 1995), which acts as an endogenous ligand at strychnine-insensitive glycinebinding site of NMDAR (Martineau et al., 2006). The striking discovery that D-serine could have therapeutic efficacy led to intensive investigations of the possible central functions of "unusual" free D-amino acids. Another D-amino acid, named D-aspartate, occurs in the mammalian brain. D-Aspartate levels are high in the embryonic phase and dramatically decrease during postnatal life, in concomitance with increased expression of D-aspartate oxidase (DDO), the enzyme responsible for its deg- radation (Schell et al., 1997;Errico et al., 2006;Huang et al., 2006). In contrast to D-serine, now well characterized for its implication in NMDAR-dependent functions, the role of D-aspartate in the CNS remains elusive.We have shown previously that D-aspartate enhances hippocampal NMDAR-dependent long-term potentiation (LTP) (Errico et al., 2008a). In the present work, we examined whether higher levels of this in-embryo-occurring molecule might increase glutamatergic transmission and exert antipsychotic effects in adult animals. Using genetic and pharmacological interventions able to enhance D-aspartate levels, we tested the ability of this D-amino acid to modulate cognition and gating abilities, which are thought, when altered, to be in...

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Section: Discussionmentioning

confidence: 78%

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

et al. 2008

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“…It is worth noting that individual vulnerability to cocaine's sensitization is also associated to a higher risk to cocaine-induced psychosis (Satel et al, 1991;Brady et al, 1991;Bartlett et al, 1997), pointing to a possible relationship between DAAO activity and sensitization. Recently, it has been reported that knockout mice that lack DAAO activity present enhanced NMDAR function together with increased occupancy of the NMDAR glycine site due to elevated extracellular D-serine levels (Almond et al, 2006). This latter fact otherwise supports that NMDA receptors are not saturated by D-serine under physiological conditions in rodents (Fuchs et al, 2005).…”

Section: Discussionmentioning

confidence: 91%

Role for D-Serine within the Ventral Tegmental Area in the Development of Cocaine's Sensitization

Fernández-Espejo

Ramiro-Fuentes

Portavella

et al. 2007

Neuropsychopharmacol

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Repeated exposure to cocaine results in motor sensitization that, in the ventral tegmental area (VTA), is associated to enhanced glutamate release, which in turn leads to enhanced calcium levels in dopaminergic neurons. Calcium influx activates calcium-calmodulindependent protein kinases such as CaMKII. D-Serine could participate on these effects, and the objective was to discern the role of VTA D-serine after a sensitizing regimen of cocaine (10 mg/kg daily), and to discern consequent expression changes in CaMKII and its activated form. For this purpose, D-serine, sodium benzoate (inhibitor of D-amino acid oxidase, the degradating enzyme of D-serine), and 7-chlorokynurenate (inhibitor of the glycine site of NMDA receptors) were injected into the VTA (in either the induction or expression phase of sensitization), and activation state of CaMKII was assessed through blotting. The findings indicated that intra-VTA administration of D-serine (5 mM) and sodium benzoate (100 and 200 mg/ml) during the induction phase (not expression) reliably augmented the expression of behavioral sensitization to cocaine, providing evidence that D-serine in the VTA participates in the initiation of motor sensitization to this psychostimulant drug. Intra-VTA infusions of D-serine, sodium benzoate and 7-chlorokynurenate did not elicit a motor effect of their own. Confirming the important role of NMDA receptors and their activation at the glycine site, the employment of 7-chlorokynurenate (2 and 5 mg/ml) led to blocking of the development of sensitization to cocaine. CaMKII within the VTA was found to participate in D-serine's effects because this kinase, that is activated after repeated cocaine, was further activated after co-treatment with D-serine or sodium benzoate. Besides CaMKII activity was otherwise reduced by 7-chlorokynurenate.

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“…1A), spinal motoneuron degeneration (Fig. 1 B-D), and abnormal locomotor activity (14). Although more detailed studies are required for full characterization of the motor phenotype in the B6 DAO −/− mice, the B6 DAO −/− mice may bear a pathophysiological resemblance to the classical adult onset familial ALS associated with R199W-DAO, in which DAO activity is at trace level.…”

Section: Discussionmentioning

confidence: 99%

“…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.

181

145

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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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Behavioral and biochemical characterization of a mutant mouse strain lacking d-amino acid oxidase activity and its implications for schizophrenia

Cited by 97 publications

References 54 publications

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

Role for D-Serine within the Ventral Tegmental Area in the Development of Cocaine's Sensitization

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

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