Metabotropic glutamate receptor and fragile x signaling in a female model of escalated aggression

Laura E. Been, Kelsey M. Moore, Bruce C. Kennedy, Robert L. Meisel

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Background Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on nucleus accumbens (NAc) neurons. We hypothesized that the activation of group I metabotropic glutamate receptor signaling though the fragile X mental retardation protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation. Methods Female hamsters were given five daily aggression tests with or without prior treatment with the metabotropic glutamate receptor 5 (mGluR5) antagonist 2-methyl-6-(phenylethynyl)-pyridine. Following aggression testing, messenger RNA expression and protein levels were measured in the nucleus accumbens for postsynaptic density protein 95 (PSD-95) and SAP90/PSD-95-associated protein 3, as well as the levels of phosphorylated FMRP. Results Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc, which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins PSD-95 and SAP90/PSD-95-associated protein 3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor. Conclusions Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathologic aggression in both female and male subjects.

Original languageEnglish (US)
Pages (from-to)685-692
Number of pages8
JournalBiological psychiatry
Issue number8
StatePublished - Apr 15 2016

Bibliographical note

Funding Information:
Research presented here was supported by National Institutes of Health Grant No. R01DA013680 (to RLM) and also by the National Institute on Drug Abuse of the National Institutes of Health under Award Number T32DA007234 (to LEB and KMM) and T32GM008471 (to KMM).

Publisher Copyright:
© 2016 Society of Biological Psychiatry.


  • Aggression
  • Fragile X
  • Nucleus accumbens
  • PSD-95
  • Plasticity
  • mGluR5


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