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 of dystrophic microglia and reactive astrocytes. In addition, prolonged elevation of D-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampal GluN1 and GluN2B subunits selectively located at synaptic sites and to increase in the aamino-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.

D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain

PAOLONE, Giovanna;LONGO, Francesco;MORARI, Michele;
2015

Abstract

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 of dystrophic microglia and reactive astrocytes. In addition, prolonged elevation of D-Asp triggered in mutants alterations of NMDAR-dependent synaptic plasticity associated to reduction of hippocampal GluN1 and GluN2B subunits selectively located at synaptic sites and to increase in the aamino-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.
Cristino, Luigia; Luongo, Livio; Squillace, Marta; Paolone, Giovanna; Mango, Dalila; Piccinin, Sonia; Zianni, Elisa; Imperatore, Roberta; Iannotta, Monica; Longo, Francesco; Errico, Francesco; Vescovi, Angelo Luigi; Morari, Michele; Maione, Sabatino; Gardoni, Fabrizio; Nisticò, Robert; Usiello, Alessandro
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2334540
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