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.
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Errico
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: V
authors.initials: V
authors.lastname: D'Argenio
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Sforazzini
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine 'Federico II', Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Iasevoli
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Squillace
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Guerri
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy [2] IEOS, CNR, Naples, Italy [3] Department of Biology, University of Naples 'Federico II', Naples, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Angrisano
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Di Maio
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy [2] IEOS, CNR, Naples, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Keller
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Vitucci
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Galbusera
authors.affiliation: 1] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy [2] IEOS, CNR, Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Chiariotti
authors.affiliation: 1] Group of Psychiatric Neuroscience, Department of Neuroscience, Basic Sciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] pRED, Neuroscience DTA, Hoffman-La Roche, Ltd, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, University School of Medicine 'Federico II', Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: de Bartolomeis
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy [3] IRCCS-Fondazione SDN, Via Gianturco, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Salvatore
authors.affiliation: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gozzi
authors.affiliation: 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Usiello
mesh_terms: D000328:Adult; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D050804:D-Aspartate Oxidase / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D059907:Functional Neuroimaging; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010622:Phencyclidine / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D065808:Prepulse Inhibition / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia
chemical_list: D018691:Excitatory Amino Acid Antagonists; D050804:D-Aspartate Oxidase; C494102:DDO protein, human; D010622:Phencyclidine