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Errico F.,Laboratory of Behavioural Neuroscience | Errico F.,University of Naples Federico II | Nistico R.,Cervello | Nistico R.,University of Rome La Sapienza | And 21 more authors.
Translational Psychiatry | Year: 2014

D-aspartate (D-Asp) is an atypical amino acid, which is especially abundant in the developing mammalian brain, and can bind to and activate N-methyl-D-Aspartate receptors (NMDARs). In line with its pharmacological features, we find that mice chronically treated with D-Asp show enhanced NMDAR-mediated miniature excitatory postsynaptic currents and basal cerebral blood volume in fronto-hippocampal areas. In addition, we show that both chronic administration of D-Asp and deletion of the gene coding for the catabolic enzyme D-aspartate oxidase (DDO) trigger plastic modifications of neuronal cytoarchitecture in the prefrontal cortex and CA1 subfield of the hippocampus and promote a cytochalasin D-sensitive form of synaptic plasticity in adult mouse brains. To translate these findings in humans and consistent with the experiments using Ddo gene targeting in animals, we performed a hierarchical stepwise translational genetic approach. Specifically, we investigated the association of variation in the gene coding for DDO with complex human prefrontal phenotypes. We demonstrate that genetic variation predicting reduced expression of DDO in postmortem human prefrontal cortex is mapped on greater prefrontal gray matter and activity during working memory as measured with MRI. In conclusion our results identify novel NMDAR-dependent effects of D-Asp on plasticity and physiology in rodents, which also map to prefrontal phenotypes in humans. © 2014 Macmillan Publishers Limited. Source


Errico F.,Laboratory of Behavioural Neuroscience | Errico F.,University of Naples Federico II | Di Maio A.,Laboratory of Behavioural Neuroscience | Marsili V.,Laboratory of Behavioural Neuroscience | And 6 more authors.
Journal of Biological Regulators and Homeostatic Agents | Year: 2013

Nowadays it is widely recognized that D-amino acids are present in bacteria as well as in eukaryotes, including mammals. In particular, free D-serine and D-aspartate are found in the brain of mammals. Notably, D-aspartate occurs at substantial levels in the embryo brain to then consistently decrease at post-natal phases. Temporal regulation of D-aspartate content depends on the post-natal onset of D-aspartate oxidase expression, the only known enzyme able to catabolize this D-amino acid. Pharmacological evidence indicates that D-aspartate binds and activates NMDA receptors (NMDARs). To decipher the physiological function of D-aspartate in mammals, in the last years, genetic and pharmacological mouse models with abnormally higher levels of this D-amino acid have been generated. Overall, these animal models have pointed out a significant neuromodulatory role for D-aspartate in the regulation of NMDAR-dependent functions. Indeed, increased content of D-aspartate are able to increase hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory of adult mice. However, if exposure to elevated levels of D-Asp lasts for the entire lifetime of mice, enhancement of synaptic plasticity turns into a dramatic worsening, thus triggering an acceleration of the NMDAR-dependent aging processes in the hippocampus. Nonetheless, administration of D-Asp to old mice can restore the physiological age-related decay of hippocampal NMDA-related LTP. Besides its effect on hippocampus-dependent processes in mouse models, different points of evidence are indicating, today, a potential role for D-Asp in neurologic and psychiatric disorders associated with aberrant signalling of NMDARs. Copyright © by BIOLIFE, s.a.s. Source


Boccella S.,The Second University of Naples | Vacca V.,National Research Council Italy | Errico F.,Laboratory of Behavioural Neuroscience | Errico F.,University of Naples Federico II | And 11 more authors.
BioMed Research International | Year: 2015

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo -/-) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo -/- mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo -/- mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4-L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions. © 2015 Serena Boccella et al. Source


Errico F.,Laboratory of Behavioural Neuroscience | Errico F.,University of Naples Federico II | Mothet J.-P.,Aix - Marseille University | Usiello A.,Laboratory of Behavioural Neuroscience | Usiello A.,The Second University of Naples
Journal of Pharmaceutical and Biomedical Analysis | Year: 2015

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. © 2015 Elsevier B.V. Source


Cristino L.,National Research Council Italy | Luongo L.,The Second University of Naples | Squillace M.,Laboratory of Behavioural Neuroscience | Paolone G.,University of Ferrara | And 16 more authors.
Neurobiology of Aging | Year: 2015

We have investigated the relevance of d-aspartate oxidase, the only enzyme known to selectively degrade d-aspartate (d-Asp), in modulating glutamatergic system homeostasis. Interestingly, the lack of the Ddo gene, by raising d-Asp content, induces a substantial increase in extracellular glutamate (Glu) levels in Ddo-mutant brains. Consistent with an exaggerated and persistent N-methyl-d-aspartate receptor (NMDAR) stimulation, we documented in Ddo knockouts severe age-dependent structural and functional alterations mirrored by expression of active caspases 3 and 7 along with appearance ofdystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampalGluN1 and GluN2B subunits selectively located at synaptic sites and to increase in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-to-N-methyl-d-aspartate ratio. These effects, all of which converged on a progressive hyporesponsiveness at NMDAR sites, functionally resulted in a greater vulnerability to phencyclidine-induced prepulse inhibition deficits in mutants. In conclusion, our results indicate that d-aspartate oxidase, by strictly regulating d-Asp levels, impacts on the homeostasis of glutamatergic system, thus preventing accelerated neurodegenerative processes. © 2015 Elsevier Inc. Source

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