D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain

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.