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The Journal of Neuroscience, October 8, 2008, 28(41):10404-10414; doi:10.1523/JNEUROSCI.1618-08.2008

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Behavioral/Systems/Cognitive
D-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

Francesco Errico,^1 * Silvia Rossi,^2,3 * Francesco Napolitano,¹ Valeria Catuogno,¹ Enza Topo,⁴ Gilberto Fisone,⁵ Antimo D'Aniello,⁴ Diego Centonze,^2,3 and Alessandro Usiello^1,6

¹Laboratory of Behavioural Neuroscience, Centro Ingegneria Genetica Biotecnologie Avanzate, 80145 Naples, Italy, ²Clinica Neurologica, Università Tor Vergata, 00133 Rome, Italy, ³Centro Europeo per la Ricerca sul Cervello/Fondazione Santa Lucia, 00179 Rome, Italy, ⁴Department of Neurobiology, Stazione Zoologica "A. Dohrn," 80121 Naples, Italy, ⁵Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden, and ⁶Department of Health Science, Università del Molise, 86100 Campobasso, Italy

Correspondence should be addressed to Alessandro Usiello, CEINGE Biotecnologie Avanzate, Via ComunaleMargherita 482, 80145 Naples, Italy. Email: usiello{at}ceinge.unina.it

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.

Key words: D-aspartate; NMDA receptors; schizophrenia; synaptic plasticity; prepulse inhibition; spatial memory; D-serine

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Received Aug. 14, 2008; accepted Sept. 4, 2008.

Correspondence should be addressed to Alessandro Usiello, CEINGE Biotecnologie Avanzate, Via ComunaleMargherita 482, 80145 Naples, Italy. Email: usiello{at}ceinge.unina.it

This article has been cited by other articles:

				G. Martella, A. Tassone, G. Sciamanna, P. Platania, D. Cuomo, M. T. Viscomi, P. Bonsi, E. Cacci, S. Biagioni, A. Usiello, et al. Impairment of bidirectional synaptic plasticity in the striatum of a mouse model of DYT1 dystonia: role of endogenous acetylcholine Brain, September 1, 2009; 132(9): 2336 - 2349. [Abstract] [Full Text] [PDF]

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