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 - 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
SN - 0197-4580
VL - 36
SP - 1890
EP - 1902
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 5
ER -