TY - JOUR
T1 - D-aspartate prevents corticostriatal long-term depression and attenuates schizophrenia-like symptoms induced by amphetamine and MK-801
AU - Errico, Francesco
AU - Rossi, Silvia
AU - Napolitano, Francesco
AU - Catuogno, Valeria
AU - Topo, Enza
AU - Fisone, Gilberto
AU - D'Aniello, Antimo
AU - Centonze, Diego
AU - Usiello, Alessandro
PY - 2008/10/8
Y1 - 2008/10/8
N2 - 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.
AB - 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.
KW - D-aspartate
KW - D-serine
KW - NMDA receptors
KW - Prepulse inhibition
KW - Schizophrenia
KW - Spatial memory
KW - Synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=55249126223&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=55249126223&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1618-08.2008
DO - 10.1523/JNEUROSCI.1618-08.2008
M3 - Article
C2 - 18842900
AN - SCOPUS:55249126223
VL - 28
SP - 10404
EP - 10414
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 41
ER -