title: d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain.
abstract: 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 of dystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampal GluN1 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.
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Cristino
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Squillace
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Paolone
authors.affiliation: European Center for Brain Research, Rome, Italy.
authors.forename: Dalila
authors.initials: D
authors.lastname: Mango
authors.affiliation: European Center for Brain Research, Rome, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Piccinin
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Zianni
authors.affiliation: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Imperatore
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Iannotta
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Longo
authors.affiliation: Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
authors.forename: Angelo Luigi
authors.initials: AL
authors.lastname: Vescovi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Morari
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Department of Pharmacological Sciences, University of Milan, Milan, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gardoni
authors.affiliation: European Center for Brain Research, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. Electronic address: robert.nistico@uniroma1.it.
authors.forename: Robert
authors.initials: R
authors.lastname: Nisticò
authors.affiliation: Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, The Second University of Naples (SUN), Caserta, Italy. Electronic address: usiello@ceinge.unina.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D050804:D-Aspartate Oxidase / Q000235:genetics / Q000502:physiology*; D026603:D-Aspartic Acid / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000517:prevention & control; D009473:Neuronal Plasticity / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D026603:D-Aspartic Acid; D050804:D-Aspartate Oxidase; C494102:DDO protein, human; D053148:Caspase 3; D053179:Caspase 7
keywords: Glutamate; Hippocampus; Microglia; Prefrontal cortex; d-aspartate; d-aspartate oxidase