The Emerging Role of Altered d-Aspartate Metabolism in Schizophrenia: New Insights From Preclinical Models and Human Studies

Abstract

Besides d-serine, another d-amino acid with endogenous occurrence in the mammalian brain, d-aspartate, has been recently shown to influence NMDA receptor (NMDAR)-mediated transmission. d-aspartate is present in the brain at extracellular level in nanomolar concentrations, binds to the agonist site of NMDARs and activates this subclass of glutamate receptors. Along with its direct effect on NMDARs, d-aspartate can also evoke considerable l-glutamate release in specific brain areas through the presynaptic activation of NMDA, AMPA/kainate and mGlu5 receptors. d-aspartate is enriched in the embryonic brain of rodents and humans and its concentration strongly decreases after birth, due to the post-natal expression of the catabolising enzyme d-aspartate oxidase (DDO). Based on the hypothesis of NMDAR hypofunction in schizophrenia pathogenesis, recent preclinical and clinical studies suggested a relationship between perturbation of d-aspartate metabolism and this psychiatric disorder. Consistently, neurophysiological and behavioral characterization of Ddo knockout (Ddo−/−) and d-aspartate-treated mice highlighted that abnormally higher endogenous d-aspartate levels significantly increase NMDAR-mediated synaptic plasticity, neuronal spine density and memory. Remarkably, increased d-aspartate levels influence schizophrenia-like phenotypes in rodents, as indicated by improved fronto-hippocampal connectivity, attenuated prepulse inhibition deficits and reduced activation of neuronal circuitry induced by phencyclidine exposure. In healthy humans, a genetic polymorphism associated with reduced prefrontal DDO gene expression predicts changes in prefrontal phenotypes including greater gray matter volume and enhanced functional activity during working memory. Moreover, neurochemical detections in post-mortem brain of schizophrenia-affected patients have shown significantly reduced d-aspartate content in prefrontal regions, associated with increased DDO mRNA expression or DDO enzymatic activity. Overall, these findings suggest a possible involvement of dysregulated embryonic d-aspartate metabolism in schizophrenia pathophysiology and, in turn, highlight the potential use of free d-aspartate supplementation as a new add-on therapy for treating the cognitive symptoms of this mental illness.

d-amino Acids in Health and Disease: A Focus on Cancer

“…Multiple meta-analyses indicate that NMDA receptor agonists including d -Ser enhance anti-schizophrenic effects in clinical trials [127,128,129]. Furthermore, recent research also suggests that altered d -Asp release is linked to the development of schizophrenia [130]. For example, decreased d -Asp levels are found in the prefrontal cortex of post-mortem brains from schizophrenic patients compared to controls [131,132].…”

The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson’s disease patients

“…In the mammalian brain, besides the main excitatory amino acid L-glutamate (L-Glu), two amino acids in D configuration, D-serine (D-Ser) and D-aspartate (D-Asp), are known to influence NMDAR-mediated transmission. In particular, D-Ser is known to stimulate the glycine-binding site of NMDARs 14,15 , while D-Asp binds to the glutamate site of this receptor subclass 16 . Conversely, their respective L-enantiomers, L-Ser and L-Asp, serve mainly as building blocks of proteins and metabolic intermediates 17,18 .…”

“…D-Ser is generated from L-Ser by the pyridoxal phosphate (PLP)-dependent enzyme serine racemase (SR) 20,21 , and its degradation occurs through an oxidative deamination catalyzed by D-amino acid oxidase (DAAO) 22,23 . Conversely, the precise mechanism underlying the endogenous production of D-Asp is not yet understood, although it is well established that its degradation is catalyzed by D-aspartate oxidase (DDO) enzyme 16,24 . So far, only a few investigations have addressed the involvement of these D-amino acids in the dysfunctional glutamate transmission found in PD.…”

Binding and transport of D-aspartate by the glutamate transporter homolog GltTk

“…Such a role is also proposed for L-aspartate (Cavallero et al, 2009), however this is still a matter of debate (Herring et al, 2015). Both stereoisomers bind to and activate N-methyl-D-aspartate receptors (NMDARs) (Patneau and Mayer, 1990) and might be involved in learning and memory processes (reviewed in Errico et al, 2018; Errico and Usiello, 2017; Katane and Homma, 2011; Ota et al, 2012).…”