D-Aspartate oxidase influences glutamatergic system homeostasis in mammalian brain

NEUROBIOLOGY OF AGING

卷:36

Article

Cristino, Luigia¹  Luongo, Livio²  Squillace, Marta³  Paolone, Giovanna^4,5  Mango, Dalila⁶  Piccinin, Sonia⁶  Zianni, Elisa⁷  Imperatore, Roberta¹  Iannotta, Monica²  Longo, Francesco^4,5  Errico, Francesco^3,8  Vescovi, Angelo Luigi⁹  Morari, Michele^4,5  Maione, Sabatino²  Gardoni, Fabrizio⁷  Nistico, Robert^6,10  Usiello, Alessandro^3,11 

[1] CNR, Endocannabinoid Res Grp, Inst Biomol Chem, Pozzuoli, Italy

[2] Univ Naples 2, Dept Expt Med, Pharmacol Sect, Naples, Italy

[3] CEINGE Biotecnol Avanzate, Lab Behav Neurosci, I-80145 Naples, Italy

[4] Univ Ferrara, Dept Med Sci, Pharmacol Sect, I-44100 Ferrara, Italy

[5] Natl Inst Neurosci, Ferrara, Italy

[6] European Ctr Brain Res, Rome, Italy

[7] Univ Milan, Dept Pharmacol Sci, Milan, Italy

[8] Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy

[9] Ist Ricovero & Cura Carattere Sci Casa Sollievo d, San Giovanni Rotondo, Italy

[10] Univ Roma La Sapienza, Dept Physiol & Pharmacol, I-00185 Rome, Italy

[11] SUN, Dept Environm Biol & Pharmaceut Sci & Technol, Caserta, Italy

关键词: D-aspartate;    D-aspartate oxidase;    Glutamate;    Microglia;    Hippocampus;    Prefrontal cortex;   

DOI  :  10.1016/j.neurobiolaging.2015.02.003

来源: Elsevier

【 摘 要 】

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 alpha-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. (C) 2015 Elsevier Inc. All rights reserved.

【 授权许可】

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