A physiological mechanism to regulate d-aspartic acid and NMDA levels in mammals revealed by d-aspartate oxidase deficient mice

Errico, Francesco; Pirro, Maria Teresa; Affuso, Andrea; Spinelli, Patrizia; Felice, Mario De; D’Aniello, Antimo; Lauro, Roberto Di

doi:10.1016/j.gene.2006.01.010

Cited by 63 publications

(71 citation statements)

References 28 publications

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“…and 2 month chronically treated mice Recently, two independent laboratories have demonstrated that ablation of the Ddo gene, obtained by genetic homologous re-combination, results in a substantial increase of D-aspartate levels in adult mutant mice (Errico et al, 2006;Huang et al, 2006). These data, observed both in endocrine glands and in the brain, clearly demonstrated a pivotal role for DDO in controlling the physiological content of D-aspartate in mammals.…”

Section: High Levels Of D-aspartate In Discrete Brain Regions Of Ddomentioning

confidence: 96%

“…Mutant mice for the Ddo gene were generated as described previously (Errico et al, 2006). Four-month-old male wild-type (Ddo ϩ/ϩ ) and knock-out (Ddo Ϫ/Ϫ ) mice were used in this study and derived from mating of heterozygous (Ddo ϩ/Ϫ ) mice, back-crossed to the F5 generation to C57BL/6J strain (Silva et al, 1997).…”

Section: Animalsmentioning

confidence: 99%

“…Four-month-old male wild-type (Ddo ϩ/ϩ ) and knock-out (Ddo Ϫ/Ϫ ) mice were used in this study and derived from mating of heterozygous (Ddo ϩ/Ϫ ) mice, back-crossed to the F5 generation to C57BL/6J strain (Silva et al, 1997). Animals were genotyped by PCR according to Errico et al (2006). C57BL/6J male mice were used to test the effects of 2 months of oral administration of D-aspartate in neurochemical, behavioral, biochemical, and electrophysiological studies.…”

Section: Animalsmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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: High Levels Of D-aspartate In Discrete Brain Regions Of Ddomentioning

confidence: 96%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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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“…23 Because D-Asp concentration is regulated by DDO, 26,35,36 we measured the levels of DDO mRNA in the PFC of SCZ patients by qRT-PCR. Statistical analysis revealed a significant increase in DDO mRNA of patients D-aspartate affects schizophrenia-related symptoms F Errico et al with SCZ, compared with healthy subjects (P = 0.0020, analysis of covariance with covariance for postmortem delay, Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Squillace

Errico

D’Argenio

et al. 2015

European Psychiatry

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Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo −/ − ), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo − / − mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo − / − animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

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Chiral separation of N‐methyl‐dl‐aspartic acid in rat brain tissue as N‐ethoxycarbonylated (S)‐(+)‐2‐octyl ester derivatives by GC‐MS

Nguyen

Kim

Lee

et al. 2012

Biomedical Chromatography

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A selective and sensitive analytical method was developed for enantiomeric separation and determination of N-methyl-DL-aspartic acid (NMA). The method involved the conversion of each enantiomer into N-ethoxycarbonylated (S)-(+)-2-octyl ester derivative for the direct separation by gas chromatography-mass spectrometry (GC-MS). The diastereomeric derivatives showed characteristic mass spectral properties for analysis by selected ion monitoring mode (SIM) and enabling enantioseparation on an achiral capillary column. Two enantiomers were baseline separated, and the detection limits for N-methyl-L-aspartic acid (NMLA) and N-methyl-D-aspartic acid (NMDA) were 0.07 and 0.03 ng/g, respectively. When applied to rat brain tissues for absolute configuration of NMA, only NMDA was determined, while NMLA was monitored as lower than the limit of detection.

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A physiological mechanism to regulate d-aspartic acid and NMDA levels in mammals revealed by d-aspartate oxidase deficient mice

Cited by 63 publications

References 28 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

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Chiral separation of N‐methyl‐dl‐aspartic acid in rat brain tissue as N‐ethoxycarbonylated (S)‐(+)‐2‐octyl ester derivatives by GC‐MS

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