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Mol Psychiatry. 2018 Aug 8. doi: 10.1038/s41380-018-0132-3. [Epub ahead of print]

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

Author information

1
Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, EPFL, Lausanne, Switzerland.
2
Laboratory of Synaptic Mechanisms, Brain Mind Institute, EPFL, Lausanne, Switzerland.
3
Laboratory of Neuroepigenetics, Brain Mind Institute, EPFL, Lausanne, Switzerland.
4
Interdisciplinary Centre for Electron Microscopy, EPFL, Lausanne, Switzerland.
5
Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, EPFL, Lausanne, Switzerland. carmen.sandi@epfl.ch.

Abstract

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.

PMID:
30089788
DOI:
10.1038/s41380-018-0132-3

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