Chronic Administration of AFQ056/Mavoglurant Restores Social Behaviour in Fmr1 Knockout Mice

Behav Brain Res. 2013 Feb 15;239:72-9. doi: 10.1016/j.bbr.2012.10.059. Epub 2012 Nov 6.

Abstract

Fragile X syndrome is caused by lack of FMR1 protein (FMRP) leading to severe symptoms, including intellectual disability, hyperactivity and autistic-like behaviour. FMRP is an RNA binding protein involved in the regulation of translation of specific target mRNAs upon stimulation of metabotropic glutamate receptor 5 (mGluR5) at the synapse. The absence of FMRP leads to enhanced activity of mGluR5 signal transduction pathways. Many conflicting results have been reported regarding social behaviour deficits in Fmr1 knockout mice, and little is known about the involvement of mGluR5 pathways on social behaviour. In this study, a three-chambered task was used to determine sociability and preference for social novelty in Fmr1 knockout mice. Disruption of Fmr1 functioning resulted in enhanced interaction with stranger mouse during sociability while no significant changes were observed during preference for social novelty assay. Chronic administration of a specific mGluR5 antagonist, AFQ056/Mavoglurant, was able to restore sociability behaviour of Fmr1 knockout mice to levels of wild type littermates. These results support the importance of mGluR5 signalling pathways on social interaction behaviour and that AFQ056/Mavoglurant might be useful as potential therapeutic intervention to rescue various behavioural aspects of the fragile X phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / physiology*
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Indoles / pharmacology*
  • Indoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Social Behavior*
  • Time Factors

Substances

  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Grm5 protein, mouse
  • Indoles
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein
  • mavoglurant