Mechanism-based approaches to treating fragile X

Pharmacol Ther. 2010 Jul;127(1):78-93. doi: 10.1016/j.pharmthera.2010.02.008. Epub 2010 Mar 18.


Fragile X is the leading inherited cause of mental retardation and autism. Recent advances in our mechanistic understanding of the disease have led to the identification of the metabotropic glutamate receptor (mGluR) as a therapeutic target for the disease. These studies have revealed that core defects in multiple animal models can be corrected by down regulation of mGluR5 signaling. Although it remains to be seen if mGluR5 antagonists or related approaches will succeed in humans with fragile X, the progress in fragile X stands as a strong testament to the power of applying knowledge of basic neurobiology to understand pathophysiology in a genetically validated model of human psychiatric disease. These breakthroughs and several of the resulting drug development efforts are reviewed.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / physiopathology
  • Clinical Trials as Topic
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / metabolism*
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology
  • Humans
  • Male
  • Mice
  • Neuronal Plasticity
  • Rats
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / drug effects


  • GRM5 protein, human
  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein