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

Chih-Hua Chang1, Chun-Lin Su1, Po-Wu Gean1

  • 1Department of Pharmacology, National Cheng-Kung University, Tainan, 701, Taiwan.

Neuropharmacology
|September 24, 2018
PubMed

Insights

Blocking NMDA receptors (NMDARs) in the ventral hippocampus reduces impulsive aggression by increasing brain-derived neurotrophic factor (BDNF) expression. This mechanism involves protein phosphatase 2A (PP2A) and dephosphorylation of eEF2.

Area of Science:

  • Neuroscience
  • Behavioral Neuroscience
  • Molecular Psychiatry

Background:

  • Impulsive aggression is a significant concern, particularly under stress.
  • Previous research indicated NMDA receptor (NMDAR) blockade in the ventral hippocampus (VH) reduces aggression.
  • The precise mechanisms underlying this anti-aggressive effect remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which NMDAR blockade in the VH attenuates stress-provoked attack behavior.
  • To investigate the role of brain-derived neurotrophic factor (BDNF) and its regulatory pathways in this process.

Main Methods:

  • Administration of NMDAR antagonist MK-801 and eEF2 kinase inhibitor NH125 into the VH of mice.
  • Assessment of attack behavior in post-weaning socially isolated mice.
  • Measurement of phosphorylated eukaryotic elongation factor 2 (p-eEF2) and BDNF expression.
  • Investigation of protein phosphatase 2A (PP2A) activity and the effects of its inhibition.

Main Results:

  • MK-801 administration decreased p-eEF2 and increased BDNF expression in the VH.
  • NH125 infusion reduced attack behavior and increased BDNF expression.
  • BDNF knockdown in the VH abolished the anti-aggressive effects of MK-801 and NH125.
  • MK-801 increased PP2A activity, and PP2A inhibition blocked its anti-aggressive effects.

Conclusions:

  • NMDAR blockade reduces attack behavior via enhanced PP2A activity, leading to eEF2 dephosphorylation and increased BDNF expression in the VH.
  • Increased BDNF expression is a key factor in mitigating impulsive aggression.
  • Targeting this pathway may offer therapeutic benefits for individuals at risk of impulsive aggression.
Keywords:
AggressionBDNFNMDA receptorPP2AVentral hippocampuseEF2

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