Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism

International audienceBackground: Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that d-aspartate and d-serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out.Methods: Through HPLC and qPCR analyses we investigated d-aspartate and d-serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2-/-, Shank3-/-, and 16p11.2+/- mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations.Results: Biochemical and gene expression mapping in Cntnap2-/-, Shank3-/-, and 16p11.2+/- failed to find gross cerebral and serum alterations in d-aspartate and d-serine metabolism. Conversely, we found a striking and stereoselective increased d-aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of d-aspartate oxidase, encoding the enzyme responsible for d-aspartate catabolism.Conclusions: Our results demonstrated the presence of disrupted d-aspartate metabolism in a widely used animal model of idiopathic ASD.General significance: Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders

Identification of Novel d‑Aspartate Oxidase Inhibitors by <i>in Silico</i> Screening and Their Functional and Structural Characterization <i>in Vitro</i>

d-Aspartate oxidase (DDO) is a degradative enzyme that is stereospecific for acidic d-amino acids, including d-aspartate, a potential agonist of the <i>N</i>-methyl-d-aspartate (NMDA) receptor. Dysfunction of NMDA receptor-mediated neurotransmission has been implicated in the onset of various mental disorders, such as schizophrenia. Hence, a DDO inhibitor that increases the brain levels of d-aspartate and thereby activates NMDA receptor function is expected to be a useful compound. To search for potent DDO inhibitor(s), a large number of compounds were screened <i>in silico</i>, and several compounds were identified as candidates. They were then characterized and evaluated as novel DDO inhibitors <i>in vitro</i> (e.g., the inhibitor constant value of 5-aminonicotinic acid for human DDO was 3.80 μM). The present results indicate that some of these compounds may serve as lead compounds for the development of a clinically useful DDO inhibitor and as active site probes to elucidate the structure–function relationships of DDO