10 μg sh-St8sia2 or control plasmid DNA were diluted in a sterile solution of 5% glucose to a final volume of 16.8 μL and complexed with 3.2 μL of linear PEI. Pups were anesthetized and placed in a stereotaxic frame, using a three-dimensional printed model of P2 body shape. The insertion point of the 30-gauge injection needle was 0.7 mm lateral to the superior sagittal sinus and ± 2.0 mm rostral to the lambda. The needle was inserted to a depth of 3.5 mm from the surface of the skin. PEI–plasmid complex (0.2 μL) were injected using a 5 μL Hamilton syringe. After 5 min, the needle was withdrawn slowly.

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.