d-Aspartate Prevents Corticostriatal Long-Term Depression and Attenuates Schizophrenia-Like Symptoms Induced by Amphetamine and MK-801

Abstract

IntroductionSchizophrenia (SCZ) is a severe mental disorder afflicting ϳ1% of the population worldwide. Despite decades of intensive research, the precise etiology of this devastating mental illness remains, so far, an unresolved puzzle (Sawa and Snyder, 2002). It has been proposed that dysfunction of dopaminergic neurotransmission occurs in SCZ patients (Snyder, 1976); however, a large body of evidence recently proposed that abnormal serotonergic and glutamatergic neurotransmission might also be implicated in the pathophysiological processes leading to the development of schizophrenia (González-Maeso et al., 2008). Compelling evidence from genetic, brain imaging, and clinical studies strongly suggests that psychotic symptoms might be associated with a persistent hypoglutamatergic transmission involving reduced NMDA receptor (NMDAR) activation (Tsai and Coyle, 2002). This hypothesis is mainly based on two fundamental observations: first, administration to healthy subjects of noncompetitive NMDAR antagonists, such as phencyclidine (PCP) or ketamine, results in severe mental symptoms resembling those of schizophrenic patients; second, administration of PCP to psychotic patients exacerbates positive and negative symptoms and worsens their cognitive functions (Javitt and Zukin, 1991;Olney and Farber, 1995). Together, these findings suggest that interventions able to enhance NMDAR transmission might be beneficial for the treatment of SCZ (Kristiansen et al., 2007). In particular, administration of D-serine to clozapine-treated patients ameliorates their positive, negative, and cognitive deficits (Tsai et al., 1999).D-Serine is a D-amino acid occurring in the mammalian forebrain throughout postnatal lifetime (Schell et al., 1995), which acts as an endogenous ligand at strychnine-insensitive glycinebinding site of NMDAR (Martineau et al., 2006). The striking discovery that D-serine could have therapeutic efficacy led to intensive investigations of the possible central functions of "unusual" free D-amino acids. Another D-amino acid, named D-aspartate, occurs in the mammalian brain. D-Aspartate levels are high in the embryonic phase and dramatically decrease during postnatal life, in concomitance with increased expression of D-aspartate oxidase (DDO), the enzyme responsible for its deg- radation (Schell et al., 1997;Errico et al., 2006;Huang et al., 2006). In contrast to D-serine, now well characterized for its implication in NMDAR-dependent functions, the role of D-aspartate in the CNS remains elusive.We have shown previously that D-aspartate enhances hippocampal NMDAR-dependent long-term potentiation (LTP) (Errico et al., 2008a). In the present work, we examined whether higher levels of this in-embryo-occurring molecule might increase glutamatergic transmission and exert antipsychotic effects in adult animals. Using genetic and pharmacological interventions able to enhance D-aspartate levels, we tested the ability of this D-amino acid to modulate cognition and gating abilities, which are thought, when altered, to be in...

Characterization of the Enzymatic and Structural Properties of Human D-Aspartate Oxidase and Comparison with Those of the Rat and Mouse Enzymes

“…Indeed, DDO-deficient mice have elevated concentrations of D-Asp in several brain regions and exhibit specific antidepressant and antischizophrenic behaviors. 26,27) These findings support the concept that DDO inhibitors that activate NMDA receptor function by augmenting the levels of D-Asp in the brain would be new and useful antipsychotic drugs for the treatment of NMDA receptor-related diseases. DDO inhibitors may also be lead compounds for the development of new drugs to treat infertility since D-Asp is thought to be involved in the quality control of germ cells.…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Other studies using mutagenesis and homology modeling of GluN2A and GluN2B LBDs have suggested that NMDA cannot bind to GluA subunits because of steric clash between the N-methyl group of NMDA and Met708 in GluA2, which is conserved among all AMPA receptors (Laube et al, 2004;. GluN2 endogenous agonists include glutamate, D-and L-aspartate (Benveniste, 1989;Nicholls, 1989;Fleck et al, 1993;Schell et al, 1997;Wang and Nadler, 2007;Errico et al, 2008;Zhang and Nadler, 2009), homocysteate, and cysteinesulfinate (Do et al, 1986(Do et al, , 1988Olney et al, 1987;Yuzaki and Connor, 1999) (Table 8). Cyclic analogs with conformationally constrained rings also act as potent GluN2 agonists, in some cases with EC 50 values lower than glutamate (Shinozaki et al, 1989;Schoepp et al, 1991;Erreger et al, 2007) (Table 8).…”

Physiological evidence that d-aspartate activates a current distinct from ionotropic glutamate receptor currents in Aplysia californica neurons

“…The majority of evidence gathered so far would suggest that D-Asp is a ligand for NMDARs (Kiskin et al 1990;Olverman et al 1988). Errico et al (2008aErrico et al ( , 2008bin press) found that D-Asp activated currents via NR2A-D receptor subunits and increased long-term potentiation through NMDAR activity, yet it also activated currents independently of NMDARs, suggesting a unique D-Asp receptor. Meanwhile, Huang et al (2005) found that D-Asp did not activate AMPA/ kainate or metabotropic glutamate receptors.…”