Mechanism underlying NMDA blockade-induced inhibition of aggression in post-weaning socially isolated mice

Neuropharmacology. 2018 Dec;143:95-105. doi: 10.1016/j.neuropharm.2018.09.019. Epub 2018 Sep 20.

Abstract

When faced with stressful conditions, people with a tendency toward impulsive aggression may suddenly hurt others. We have previously shown that the blockade of NMDA receptors (NMDARs) within the ventral hippocampus (VH) produces anti-aggressive effects. However, little is known about the mechanism for tamping down stress-provoked attack behavior. Here, we report that expression of brain-derived neurotrophic factor (BDNF) after inhibition of NMDARs in the VH is required for blunting stress-provoked attack behavior in post-weaning socially isolated mice. Administration of NMDAR antagonist MK-801 decreased the phosphorylated eukaryotic elongation factor 2 (p-eEF2) and increased BDNF expression in the VH. Infusion of eEF2 kinase inhibitor NH125 to the VH decreased attack behavior and increased BDNF expression. Knockdown of BDNF in the VH blocked the anti-aggressive effect of MK-801 and NH125. Furthermore, MK-801 rapidly increased the activity of protein phosphatase 2A (PP2A). Intra-VH infusion of PP2A inhibitor okadaic acid blocked the anti-aggressive effects of MK-801. These results suggest that blockade of NMDAR reduces attack behavior through increasing PP2A activity leading to dephosphorylation of eEF2 and an increase in BDNF expression. Our findings indicate that the enhancement of BDNF expression is beneficial for preventing impulsive aggression in at-risk beings.

Keywords: Aggression; BDNF; NMDA receptor; PP2A; Ventral hippocampus; eEF2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggression / drug effects*
  • Aggression / physiology
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Dizocilpine Maleate / pharmacology*
  • Elongation Factor 2 Kinase / metabolism
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Gene Expression Regulation / drug effects
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Impulsive Behavior / drug effects
  • Impulsive Behavior / physiology
  • Male
  • Mice, Inbred C57BL
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Protein Phosphatase 2 / metabolism
  • Psychotropic Drugs / pharmacology*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Social Isolation* / psychology
  • Stress, Psychological / drug therapy
  • Stress, Psychological / metabolism
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Excitatory Amino Acid Antagonists
  • Psychotropic Drugs
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Eef2k protein, mouse
  • Elongation Factor 2 Kinase
  • Protein Phosphatase 2