New insights on the role of free D-aspartate in the mammalian brain.

Free D-aspartate (D-Asp) occurs in substantial amounts in the brain at the embryonic phase and in the first few postnatal days, and strongly decreases in adulthood. Temporal reduction of D-Asp levels depends on the postnatal onset of D-aspartate oxidase (DDO) activity, the only enzyme able to selectively degrade this D-amino acid. Several results indicate that D-Asp binds and activates N-methyl-D-aspartate receptors (NMDARs). Accordingly, recent studies have demonstrated that deregulated, higher levels of D-Asp, in knockout mice for Ddo gene and in D-Asp-treated mice, modulate hippocampal NMDAR-dependent long-term potentiation (LTP) and spatial memory. Moreover, similarly to D-serine, administration of D-Asp to old mice is able to rescue the physiological age-related decay of hippocampal LTP. In agreement with a neuromodulatory action of D-Asp on NMDARs, increased levels of this D-amino acid completely suppress long-term depression at corticostriatal synapses and attenuate the prepulse inhibition deficits produced in mice by the psychotomimetic drugs, amphetamine and MK-801. Based on the evidence which points to the ability of D-Asp to act as an endogenous agonist on NMDARs and considering the abundance of D-Asp during prenatal and early life, future studies will be crucial to address the effect of this molecule in the developmental processes of the brain controlled by the activation of NMDARs.

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.

D-aspartate regulates melanocortin formation and function: behavioral alterations in D-aspartate oxidase-deficient mice.

D-aspartate, an abundant D-amino acid enriched in neuroendocrine tissues, can be degraded by D-aspartate oxidase (Ddo). To elucidate the function of D-aspartate, we generated mice with targeted deletion of Ddo (Ddo(-/-)) and observe massive but selective augmentations of D-aspartate in various tissues. The pituitary intermediate lobe, normally devoid of D-aspartate from endogenous Ddo expression, manifests pronounced increases of immunoreactive D-aspartate in Ddo(-/-) mice. Ddo(-/-) mice show markedly diminished synthesis and levels of pituitary proopiomelanocortin/alpha-MSH, associated with decreased melanocortin-dependent behaviors. Therefore, Ddo is the endogenous enzyme that degrades D-aspartate, and Ddo-enriched organs, low in D-aspartate, may represent areas of high turnover where D-aspartate may be physiologically important.

A physiological mechanism to regulate D-aspartic acid and NMDA levels in mammals revealed by D-aspartate oxidase deficient mice.

Free D-aspartic acid and NMDA are present in the mammalian central nervous system and endocrine glands at significant concentrations, but their physiological role is still matter of debate. The only enzyme known to metabolize in vitro selectively these D-amino acids is D-aspartate oxidase (DDO). To clarify the role in vivo of the enzyme, we generated mice with targeted deletion of Ddo gene by homologous recombination. Mutated animals showed increased amounts of both D-aspartic acid and NMDA in all tissues examined demonstrating a physiological role of DDO in the regulation of their endogenous levels.

D-aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice.

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo (-/-)) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo (-/-) mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo (-/-) mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4-L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.