d-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / pathology
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • D-Aspartate Oxidase / genetics
  • D-Aspartate Oxidase / physiology*
  • D-Aspartic Acid / metabolism
  • Glutamates / metabolism*
  • Homeostasis / genetics*
  • Mice, Knockout
  • Microglia / pathology
  • Mutation*
  • Neurodegenerative Diseases / etiology
  • Neurodegenerative Diseases / prevention & control
  • Neuronal Plasticity / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism


  • Glutamates
  • Receptors, N-Methyl-D-Aspartate
  • D-Aspartic Acid
  • D-Aspartate Oxidase
  • DDO protein, human
  • Caspase 3
  • Caspase 7