D-Aspartate-Oxidase influences glutamatergic system homeostasis in mammalian brain

We have investigated the relevance of D-Aspartate Oxidase (DDO), the only enzyme known to selectively degrade 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 NMDA receptor (NMDAR) stimulation, we documented in Ddo knockouts severe age-dependent structural and functional alterations mirrored by expression of active caspase 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 AMPA/NMDA ratio. These effects, all of which converged on a progressive hypo-responsiveness at NMDAR sites, functionally resulted in a greater vulnerability to phencyclidine-induced prepulse inhibition deficits in mutants. In conclusion, our results indicate that DDO, by strictly regulating D-Asp levels, impacts on the homeostasis of glutamatergic system thus preventing accelerated neurodegenerative processes.