| 1 | Rev Neurosci 2009 -1 20: 429-40 |
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| PMID | 20397623 |
| Title | D-aspartate: an atypical amino acid with neuromodulatory activity in mammals. |
| Abstract | Within the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the DDO gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in DDO knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2015 Oct 62: 35-43 |
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| PMID | 25979765 |
| Title | D-aspartate dysregulation in Ddo(-/-) mice modulates phencyclidine-induced gene expression changes of postsynaptic density molecules in cortex and striatum. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | J. Med. Chem. 2015 Sep 58: 7328-40 |
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| PMID | 26322531 |
| Title | Identification of Novel D-Aspartate Oxidase Inhibitors by in Silico Screening and Their Functional and Structural Characterization in Vitro. |
| Abstract | D-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for acidic D-amino acids, including D-aspartate, a potential agonist of the N-methyl-D-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders, such as schizophrenia. Hence, a DDO inhibitor that increases the brain levels of D-aspartate and thereby activates NMDA receptor function is expected to be a useful compound. To search for potent DDO inhibitor(s), a large number of compounds were screened in silico, and several compounds were identified as candidates. They were then characterized and evaluated as novel DDO inhibitors in vitro (e.g., the inhibitor constant value of 5-aminonicotinic acid for human DDO was 3.80 ?M). The present results indicate that some of these compounds may serve as lead compounds for the development of a clinically useful DDO inhibitor and as active site probes to elucidate the structure-function relationships of DDO. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Transl Psychiatry 2015 -1 5: e512 |
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| PMID | 25689573 |
| Title | A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Transl Psychiatry 2015 -1 5: e512 |
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| PMID | 25689573 |
| Title | A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice. |
| Abstract | 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. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | J Pharm Biomed Anal 2015 Dec 116: 7-17 |
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| PMID | 25868730 |
| Title | D-Aspartate: An endogenous NMDA receptor agonist enriched in the developing brain with potential involvement in schizophrenia. |
| Abstract | Free D-aspartate and D-serine occur at substantial levels in the mammalian brain. D-Serine is a physiological endogenous co-agonist for synaptic N-Methyl D-Aspartate (NMDA) receptors (NMDARs), and is involved in the pathophysiology of schizophrenia. Much less is known about the biological meaning of D-aspartate. D-Aspartate is present at high levels in the embryo brain and strongly decreases at post-natal phases. Temporal reduction of D-aspartate levels depends on the post-natal onset of D-aspartate oxidase (DDO), an enzyme able to selectively catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds to and activates NMDARs. Characterization of genetic and pharmacological mouse models with abnormally higher levels of D-aspartate has evidenced that increased D-aspartate enhances hippocampal NMDAR-dependent synaptic plasticity, dendritic morphology and spatial memory. In line with the hypothesis of a hypofunction of NMDARs in the pathogenesis of schizophrenia, it has been shown that increased D-aspartate levels also improve brain connectivity, produce corticostriatal adaptations resembling those observed after chronic haloperidol treatment, and protects against prepulse inhibition deficits and abnormal circuits activation induced by psychotomimetic drugs. In healthy humans, genetic variation predicting reduced expression of DDO in post-mortem prefrontal cortex is associated with greater prefrontal gray matter and activity during working memory. On the other side, evaluation of D-aspartate content in post-mortem patients with schizophrenia has shown a significant reduction of this D-amino acid in the prefrontal cortex and striatum. Generation of mouse models with reduced embryonic levels of D-aspartate may disclose unprecedented role for D-aspartate in developmental brain processes associated with vulnerability to psychotic-like symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic |