Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2

Neuron. 2010 Apr 29;66(2):191-7. doi: 10.1016/j.neuron.2010.03.017.


Fragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination. Here, we demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. Our results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Spines / genetics
  • Dendritic Spines / metabolism*
  • Excitatory Postsynaptic Potentials / genetics
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Hippocampus / metabolism*
  • MEF2 Transcription Factors
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence, Multiphoton
  • Miniature Postsynaptic Potentials / genetics
  • Myogenic Regulatory Factors / genetics
  • Myogenic Regulatory Factors / metabolism*
  • Nerve Net / metabolism
  • Neuronal Plasticity / genetics
  • Neurons / metabolism
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Synapses / genetics
  • Synapses / metabolism*
  • Transcription, Genetic / genetics
  • Transfection


  • MEF2 Transcription Factors
  • Mef2a protein, mouse
  • Myogenic Regulatory Factors
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein