Amygdala GluN2B-NMDAR dysfunction is critical in abnormal aggression of neurodevelopmental origin induced by St8sia2 deficiency

Mol Psychiatry. 2020 Sep;25(9):2144-2161. doi: 10.1038/s41380-018-0132-3. Epub 2018 Aug 8.


Aggression is frequently observed in neurodevelopmental psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Due to a lack of understanding of its underlying mechanisms, effective treatments for abnormal aggression are still missing. Recently, genetic variations in Sialyltransferase 2 (St8sia2) have been linked to these disorders and aggression. Here we identify abnormal aggressive behaviors and concomitant blunted fear learning in St8sia2 knockout (-/-) mice. It is worth noting that the amygdala of St8sia2-/- mice shows diminished threat-induced activation, as well as alterations in synaptic structure and function, including impaired GluN2B-containing NMDA receptor-mediated synaptic transmission and plasticity. Pharmacological rescue of NMDA receptor activity in the amygdala of St8sia2-/- mice with the partial agonist D-cycloserine restores synaptic plasticity and normalizes behavioral aberrations. Pathological aggression and associated traits were recapitulated by specific amygdala neonatal St8sia2 silencing. Our results establish a developmental link between St8sia2 deficiency and a pathological aggression syndrome, specify synaptic targets for therapeutic developments, and highlight D-cycloserine as a plausible treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggression*
  • Amygdala* / metabolism
  • Animals
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Receptors, N-Methyl-D-Aspartate* / genetics
  • Receptors, N-Methyl-D-Aspartate* / metabolism
  • Sialyltransferases* / genetics


  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Sialyltransferases
  • ST8SIA2 protein, mouse