A role for D-aspartate oxidase in schizophrenia and in schizophrenia-related symptoms induced by phencyclidine in mice

• Published in: Translational psychiatry Vol. 5; no. 2; p. e512
• Main Authors: Errico, F, D'Argenio, V, Sforazzini, F, Iasevoli, F, Squillace, M, Guerri, G, Napolitano, F, Angrisano, T, Di Maio, A, Keller, S, Vitucci, D, Galbusera, A, Chiariotti, L, Bertolino, A, de Bartolomeis, A, Salvatore, F, Gozzi, A, Usiello, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.02.2015; Nature Publishing Group
• Subjects: 59/36; 631/378/340; 64/60; Adult; Animals; Behavior, Animal - drug effects; Behavioral Sciences; Biological Psychology; Brain - drug effects; Brain - metabolism; Brain - physiopathology; Case-Control Studies; D-Aspartate Oxidase - genetics; D-Aspartate Oxidase - metabolism; Disease Models, Animal; DNA Methylation; Excitatory Amino Acid Antagonists - pharmacology; Female; Functional Neuroimaging; Humans; Magnetic Resonance Imaging; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; Middle Aged; Motor Activity - drug effects; Motor Activity - genetics; Neurosciences; Original; original-article; Pharmacotherapy; Phencyclidine - pharmacology; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Prepulse Inhibition - drug effects; Prepulse Inhibition - genetics; Psychiatry; Schizophrenia
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2015.2

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.