Format

Send to

Choose Destination
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.

Author information

1
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.
2
Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, Naples, Italy.
3
Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy.
4
Department of Medical Sciences, Section of Pharmacology, University of Ferrara and National Institute of Neuroscience, Ferrara, Italy.
5
European Center for Brain Research, Rome, Italy.
6
Department of Pharmacological Sciences, University of Milan, Milan, Italy.
7
Laboratory of Behavioural Neuroscience, CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Naples, Italy.
8
Istituto di Ricovero e Cura a Carattere Scientifico "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
9
European Center for Brain Research, Rome, Italy; Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy. Electronic address: robert.nistico@uniroma1.it.
10
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: usiello@ceinge.unina.it.

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 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.

KEYWORDS:

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

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center