TY - JOUR
T1 - D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain
AU - Cristino, Luigia
AU - Luongo, Livio
AU - Squillace, Marta
AU - Paolone, Giovanna
AU - Mango, Dalila
AU - Piccinin, Sonia
AU - Zianni, Elisa
AU - Imperatore, Roberta
AU - Iannotta, Monica
AU - Longo, Francesco
AU - Errico, Francesco
AU - Vescovi, Angelo Luigi
AU - Morari, Michele
AU - Maione, Sabatino
AU - Gardoni, Fabrizio
AU - Nisticò, Robert
AU - Usiello, Alessandro
N1 - Funding Information:
The authors thank F. Napolitano, A. Di Maio, and V. Lucignano for their excellent technical support and Jean Ann Gilder (Scientific Communication srl, Naples, Italy) for editing the text. Alessandro Usiello represents the Mariano Scippacercola Foundation. Alessandro Usiello was supported by NARSAD Independent Investigator Grant from the Brain and Behavior Research Foundation (Grant nr: 20353 ). Francesco Errico was supported by grants from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (FIRB Call - Program “Futuro in Ricerca 2010” - Project nr RBFR10XCD3) and the Italian Ministero della Salute (Call Giovani Ricercatori 2009 - Project nr GR-2009–1605759). Livio Luongo was supported by grant from the Italian Ministero dell’Istruzione, dell’Università e della Ricerca (FIRB Call— Program “Futuro in Ricerca 2012” - Project nr RBFR126IGO).
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015
Y1 - 2015
N2 - 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 ofdystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampalGluN1 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.
AB - 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 ofdystrophic microglia and reactive astrocytes. In addition, prolonged elevation of d-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampalGluN1 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.
KW - D-aspartate
KW - D-aspartate oxidase
KW - Glutamate
KW - Hippocampus
KW - Microglia
KW - Prefrontal cortex
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U2 - 10.1016/j.neurobiolaging.2015.02.003
DO - 10.1016/j.neurobiolaging.2015.02.003
M3 - Article
C2 - 25771393
AN - SCOPUS:84929416519
VL - 36
SP - 1890
EP - 1902
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 5
ER -