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Neurobiol Aging. 2015 May;36(5):1890-902. doi: 10.1016/j.neurobiolaging.2015.02.003. Epub 2015 Feb 12.

d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain.

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Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy.
Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy.
Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
European Center for Brain Research, Rome, Italy.
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
European Center for Brain Research, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. Electronic address:
Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, The Second University of Naples (SUN), Caserta, Italy. Electronic address:


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 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.


Glutamate; Hippocampus; Microglia; Prefrontal cortex; d-aspartate; d-aspartate oxidase

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