title: Free D-aspartate regulates neuronal dendritic morphology, synaptic plasticity, gray matter volume and brain activity in mammals.
abstract: 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.
authors: 1] Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors: F
authors: F
authors: Errico
authors: 1] Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy [2] Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
authors: R
authors: R
authors: Nisticò
authors: Istituto di Ricovero e Cura a Carattere Scientifico 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors: A
authors: A
authors: Di Giorgio
authors: Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy.
authors: M
authors: M
authors: Squillace
authors: 1] Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy [2] Faculty of Motor Sciences, University of Naples 'Parthenope', Naples, Italy.
authors: D
authors: D
authors: Vitucci
authors: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors: A
authors: A
authors: Galbusera
authors: Pharmacology of Synaptic Plasticity Unit, European Brain Research Institute (EBRI), Rome, Italy.
authors: S
authors: S
authors: Piccinin
authors: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors: D
authors: D
authors: Mango
authors: Group of Psychiatric Neuroscience, Department of Neuroscience, Basic Sciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors: L
authors: L
authors: Fazio
authors: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors: S
authors: S
authors: Middei
authors: Group of Psychiatric Neuroscience, Department of Neuroscience, Basic Sciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors: S
authors: S
authors: Trizio
authors: 1] Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy [2] Department of Neuroscience, Tor Vergata University Hospital Foundation, Rome, Italy.
authors: N B
authors: NB
authors: Mercuri
authors: Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy.
authors: M A
authors: MA
authors: Teule
authors: 1] Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy [2] Department of Neuroscience, Tor Vergata University Hospital Foundation, Rome, Italy.
authors: D
authors: D
authors: Centonze
authors: Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto, Italy.
authors: A
authors: A
authors: Gozzi
authors: Group of Psychiatric Neuroscience, Department of Neuroscience, Basic Sciences and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors: G
authors: G
authors: Blasi
authors: 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: A
authors: A
authors: Bertolino
authors: 1] Laboratory of Behavioural Neuroscience, Ceinge Biotecnologie Avanzate, Naples, Italy [2] Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.
authors: A
authors: A
authors: Usiello
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology*; D050804:D-Aspartate Oxidase / Q000235:genetics / Q000502:physiology; D026603:D-Aspartic Acid / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D066128:Gray Matter / Q000473:pathology / Q000502:physiology*; D006624:Hippocampus / Q000473:pathology / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017397:Prefrontal Cortex / Q000473:pathology / Q000502:physiology; D014176:Protein Biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D026603:D-Aspartic Acid; D050804:D-Aspartate Oxidase