D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801.
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.
Laboratory of Behavioural Neuroscience, Centro Ingegneria Genetica Biotecnologie Avanzate, 80145 Naples, Italy.
Francesco
F
Errico
Silvia
S
Rossi
Francesco
F
Napolitano
Valeria
V
Catuogno
Enza
E
Topo
Gilberto
G
Fisone
Antimo
A
D'Aniello
Diego
D
Centonze
Alessandro
A
Usiello
D000161:Acoustic Stimulation; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D050804:D-Aspartate Oxidase / Q000172:deficiency; D026603:D-Aspartic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology; D036881:Long-Term Synaptic Depression / Q000187:drug effects*; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects; D014018:Tissue Distribution
D000697:Central Nervous System Stimulants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D026603:D-Aspartic Acid; D016291:Dizocilpine Maleate; D000661:Amphetamine; D050804:D-Aspartate Oxidase