PMID- 25689573
OWN - NLM
STAT- MEDLINE
DCOM- 20150909
LR  - 20181113
IS  - 2158-3188 (Electronic)
IS  - 2158-3188 (Linking)
VI  - 5
IP  - 2
DP  - 2015 Feb 17
TI  - A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related 
      symptoms induced by phencyclidine in mice.
PG  - e512
LID - 10.1038/tp.2015.2 [doi]
AB  - 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.
FAU - Errico, F
AU  - Errico F
AD  - 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular 
      Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, 
      Italy.
FAU - D'Argenio, V
AU  - D'Argenio V
AD  - 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular 
      Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, 
      Italy.
FAU - Sforazzini, F
AU  - Sforazzini F
AD  - Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, 
      Rovereto, Italy.
FAU - Iasevoli, F
AU  - Iasevoli F
AD  - Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, 
      University School of Medicine 'Federico II', Naples, Italy.
FAU - Squillace, M
AU  - Squillace M
AD  - Ceinge Biotecnologie Avanzate, Naples, Italy.
FAU - Guerri, G
AU  - Guerri G
AD  - Ceinge Biotecnologie Avanzate, Naples, Italy.
FAU - Napolitano, F
AU  - Napolitano F
AD  - 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular 
      Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, 
      Italy.
FAU - Angrisano, T
AU  - Angrisano T
AD  - 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.
FAU - Di Maio, A
AU  - Di Maio A
AD  - Ceinge Biotecnologie Avanzate, Naples, Italy.
FAU - Keller, S
AU  - Keller S
AD  - 1] Department of Molecular Medicine and Medical Biotechnology, University of 
      Naples 'Federico II', Naples, Italy [2] IEOS, CNR, Naples, Italy.
FAU - Vitucci, D
AU  - Vitucci D
AD  - Ceinge Biotecnologie Avanzate, Naples, Italy.
FAU - Galbusera, A
AU  - Galbusera A
AD  - Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, 
      Rovereto, Italy.
FAU - Chiariotti, L
AU  - Chiariotti L
AD  - 1] Department of Molecular Medicine and Medical Biotechnology, University of 
      Naples 'Federico II', Naples, Italy [2] IEOS, CNR, Naples, Italy.
FAU - Bertolino, A
AU  - Bertolino A
AD  - 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.
FAU - de Bartolomeis, A
AU  - de Bartolomeis A
AD  - Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, 
      University School of Medicine 'Federico II', Naples, Italy.
FAU - Salvatore, F
AU  - Salvatore F
AD  - 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.
FAU - Gozzi, A
AU  - Gozzi A
AD  - Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, 
      Rovereto, Italy.
FAU - Usiello, A
AU  - Usiello A
AD  - 1] Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Environmental, 
      Biological and Pharmaceutical Sciences and Technologies, Second University of 
      Naples (SUN), Caserta, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150217
PL  - United States
TA  - Transl Psychiatry
JT  - Translational psychiatry
JID - 101562664
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - EC 1.4.3.1 (D-Aspartate Oxidase)
RN  - EC 1.4.3.1 (DDO protein, human)
RN  - J1DOI7UV76 (Phencyclidine)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Behavior, Animal/*drug effects
MH  - Brain/drug effects/metabolism/physiopathology
MH  - Case-Control Studies
MH  - D-Aspartate Oxidase/*genetics/metabolism
MH  - DNA Methylation
MH  - Disease Models, Animal
MH  - Excitatory Amino Acid Antagonists/*pharmacology
MH  - Female
MH  - Functional Neuroimaging
MH  - Humans
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Middle Aged
MH  - Motor Activity/drug effects/genetics
MH  - Phencyclidine/*pharmacology
MH  - Prefrontal Cortex/drug effects/*metabolism/physiopathology
MH  - Prepulse Inhibition/drug effects/genetics
MH  - Schizophrenia
PMC - PMC4445752
EDAT- 2015/02/18 06:00
MHDA- 2015/09/10 06:00
PMCR- 2015/02/01
CRDT- 2015/02/18 06:00
PHST- 2014/08/04 00:00 [received]
PHST- 2014/12/19 00:00 [revised]
PHST- 2014/12/19 00:00 [accepted]
PHST- 2015/02/18 06:00 [entrez]
PHST- 2015/02/18 06:00 [pubmed]
PHST- 2015/09/10 06:00 [medline]
PHST- 2015/02/01 00:00 [pmc-release]
AID - tp20152 [pii]
AID - 10.1038/tp.2015.2 [doi]
PST - epublish
SO  - Transl Psychiatry. 2015 Feb 17;5(2):e512. doi: 10.1038/tp.2015.2.