Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome

Psychopharmacology (Berl). 2011 May;215(2):291-300. doi: 10.1007/s00213-010-2130-2. Epub 2010 Dec 23.


Rationale: Abnormal dendritic spine morphology is a significant neuroanatomical defect in fragile X mental retardation. It has been suggested that overactive group 1 metabotropic glutamate receptor (mGlu) signaling is associated with the spine dysmorphology occurring in fragile X syndrome (FXS). Thus, group 1 mGlu became a new therapeutic target for the treatment of FXS.

Objective: The purpose of this study was to identify the effect of inhibition of mGlu signaling in FXS.

Methods: We observed the changes in dendritic spines after pharmacological modulation of mGlu signaling in an Fmr1 knockout (KO) mouse model.

Results: The activation of group 1 mGlu resulted in elongation of dendritic spines in the cultured neurons derived from Fmr1 KO mice and wild-type (WT) mice. Antagonism of group 1 mGlu reduced the average spine length of Fmr1 KO neurons. Furthermore, systemic administration of the selective group 1 mGlu5 antagonist 2-methyl-6-phenylethynyl pyridine (MPEP) reduced the average spine length and density in the cortical neurons of Fmr1 KO mice at developmental age. For the adult mice, MPEP administration was less effective for the restoration of spine length. The percentage of immature spines showed a similar reduction in parallel to the changes of spine length. Temporary MPEP intervention with single-dose treatment did not show any effect.

Conclusion: These results show that MPEP administration could partially rescue the morphological deficits of dendritic spines in Fmr1 KO mice at developmental age.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Benzopyrans / pharmacology
  • Cells, Cultured
  • Dendritic Spines / drug effects*
  • Dendritic Spines / pathology*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology*
  • Hippocampus / pathology
  • Methoxyhydroxyphenylglycol / analogs & derivatives
  • Methoxyhydroxyphenylglycol / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition / drug effects
  • Neurons / pathology*
  • Neurons / ultrastructure
  • Pyridines / pharmacology
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Silver Staining / methods


  • Benzopyrans
  • Fmr1 protein, mouse
  • N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide
  • Pyridines
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor type 1
  • Fragile X Mental Retardation Protein
  • Methoxyhydroxyphenylglycol
  • 6-methyl-2-(phenylethynyl)pyridine
  • 3,4-dihydroxyphenylglycol