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EnglishWe 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.
Cristino, L., Luongo, L., Squillace, M., Paolone, G., Mango, D., Piccinin, S., et al. (2015). D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. NEUROBIOLOGY OF AGING, 36(5), 1890-1902 [10.1016/j.neurobiolaging.2015.02.003].
| Tipologia: | Articolo su rivista | |
| Citazione: | Cristino, L., Luongo, L., Squillace, M., Paolone, G., Mango, D., Piccinin, S., et al. (2015). D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain. NEUROBIOLOGY OF AGING, 36(5), 1890-1902 [10.1016/j.neurobiolaging.2015.02.003]. | |
| Lingua: | English | |
| Settore Scientifico Disciplinare: | Settore BIO/14 | |
| Revisione (peer review): | Esperti anonimi | |
| Tipo: | Articolo | |
| Rilevanza: | Rilevanza internazionale | |
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.neurobiolaging.2015.02.003 | |
| Stato di pubblicazione: | Pubblicato | |
| Data di pubblicazione: | 2015 | |
| Titolo: | D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain | |
| Autori: | ||
| Autori: | Cristino, L; Luongo, L; Squillace, M; Paolone, G; Mango, D; Piccinin, S; Zianni, E; Imperatore, R; Iannotta, M; Longo, F; Errico, F; Vescovi, A; Morari, M; Maione, S; Gardoni, F; NISTICO', RG; Usiello, A | |
| Appare nelle tipologie: | 01 - Articolo su rivista |
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