D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain

Luigia Cristino, Livio Luongo, Marta Squillace, Giovanna Paolone, Dalila Mango, Sonia Piccinin, Elisa Zianni, Roberta Imperatore, Monica Iannotta, Francesco Longo, Francesco Errico, Angelo Luigi Vescovi, Michele Morari, Sabatino Maione, Fabrizio Gardoni, Robert Nisticò, Alessandro Usiello

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)1890-1902
Number of pages13
JournalNeurobiology of Aging
Volume36
Issue number5
DOIs
Publication statusPublished - 2015

Keywords

  • D-aspartate
  • D-aspartate oxidase
  • Glutamate
  • Hippocampus
  • Microglia
  • Prefrontal cortex

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology

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