D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801

Francesco Errico, Silvia Rossi, Francesco Napolitano, Valeria Catuogno, Enza Topo, Gilberto Fisone, Antimo D'Aniello, Diego Centonze, Alessandro Usiello

Research output: Contribution to journalArticlepeer-review

Abstract

Since their discovery in the mammalian CNS, D-aspartate and D-serine have aroused a strong interest with regard to their role as putative neuromodulatory molecules. Whereas the functional role of D-serine as an endogenous coagonist of NMDA receptors (NMDARs) has been elucidated, the biological significance of D-aspartate in the brain is still mostly unclear. In the present study, we demonstrated that nonphysiological high levels of D-aspartate (1) increased in vivo NMDAR activity, (2) attenuated prepulse inhibition deficits induced by amphetamine and MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten- 5,10-imine hydrogen maleate], (3) produced striatal adaptations of glutamate synapses resembling those observed after chronic haloperidol treatment, and (4) enhanced hippocampal NMDAR-dependent memory. This evidence was obtained using two different experimental strategies that produced an abnormal increase of endogenous D-aspartate levels in the mouse: a genetic approach based on the targeted deletion of the D-aspartate oxidase gene and a pharmacological approach based on oral administration of D-aspartate. This work provides in vivo evidence of a neuromodulatory role exerted by D-aspartate on NMDAR signaling and raises the intriguing hypothesis that also this D-amino acid, like D-serine, could be used as a therapeutic agent in the treatment of schizophrenia-related symptoms.

Original languageEnglish
Pages (from-to)10404-10414
Number of pages11
JournalJournal of Neuroscience
Volume28
Issue number41
DOIs
Publication statusPublished - Oct 8 2008

Keywords

  • D-aspartate
  • D-serine
  • NMDA receptors
  • Prepulse inhibition
  • Schizophrenia
  • Spatial memory
  • Synaptic plasticity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

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