Translational Psychiatry (Aug 2022)

D-aspartate oxidase gene duplication induces social recognition memory deficit in mice and intellectual disabilities in humans

  • Barbara Lombardo,
  • Marco Pagani,
  • Arianna De Rosa,
  • Marcella Nunziato,
  • Sara Migliarini,
  • Martina Garofalo,
  • Marta Terrile,
  • Valeria D’Argenio,
  • Alberto Galbusera,
  • Tommaso Nuzzo,
  • Annaluisa Ranieri,
  • Andrea Vitale,
  • Eleonora Leggiero,
  • Anna Di Maio,
  • Noemi Barsotti,
  • Ugo Borello,
  • Francesco Napolitano,
  • Alessandra Mandarino,
  • Marco Carotenuto,
  • Uriel Heresco-Levy,
  • Massimo Pasqualetti,
  • Paolo Malatesta,
  • Alessandro Gozzi,
  • Francesco Errico,
  • Francesco Salvatore,
  • Lucio Pastore,
  • Alessandro Usiello

Journal volume & issue
Vol. 12, no. 1
pp. 1 – 12


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Abstract The D-aspartate oxidase (DDO) gene encodes the enzyme responsible for the catabolism of D-aspartate, an atypical amino acid enriched in the mammalian brain and acting as an endogenous NMDA receptor agonist. Considering the key role of NMDA receptors in neurodevelopmental disorders, recent findings suggest a link between D-aspartate dysmetabolism and schizophrenia. To clarify the role of D-aspartate on brain development and functioning, we used a mouse model with constitutive Ddo overexpression and D-aspartate depletion. In these mice, we found reduced number of BrdU-positive dorsal pallium neurons during corticogenesis, and decreased cortical and striatal gray matter volume at adulthood. Brain abnormalities were associated with social recognition memory deficit at juvenile phase, suggesting that early D-aspartate occurrence influences neurodevelopmental related phenotypes. We corroborated this hypothesis by reporting the first clinical case of a young patient with severe intellectual disability, thought disorders and autism spectrum disorder symptomatology, harboring a duplication of a chromosome 6 region, including the entire DDO gene.