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

Tommaso Nuzzo, Masae Sekine, Daniela Punzo, Mattia Miroballo, Masumi Katane, Yasuaki Saitoh, Alberto Galbusera, Massimo Pasqualetti, Francesco Errico, Alessandro Gozzi, Jean Pierre Mothet, Hiroshi Homma, Alessandro Usiello

Research output: Contribution to journalArticlepeer-review


Background: 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.

Original languageEnglish
Article number140531
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Issue number12
Publication statusPublished - Dec 2020


  • Autism spectrum disorder
  • D-aspartate
  • D-aspartate oxidase
  • D-serine
  • NMDA receptors

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology


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