Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials

Neuropharmacology. 2015 Jan;88:48-54. doi: 10.1016/j.neuropharm.2014.06.028. Epub 2014 Jul 10.


An increasing number of studies implicate the GABAAergic system in the pathophysiology of the fragile X syndrome, a frequent cause of intellectual disability and autism. Animal models have proven invaluable in unravelling the molecular mechanisms underlying the disorder. Multiple defects in this inhibitory system have been identified in Fmr1 knockout mice, including altered expression of various components, aberrant GABAA receptor-mediated signalling, altered GABA concentrations and anatomical defects in GABAergic neurons. Aberrations compatible with those described in the mouse model were detected in dfmr1 deficient Drosophila melanogaster, a validated fly model for the fragile X syndrome. Treatment with drugs that ameliorate the GABAAergic deficiency in both animal models have demonstrated that the GABAA receptor is a promising target for the treatment of fragile X patients. Based on these preclinical studies, clinical trials in patients have been initiated.

Keywords: Fragile X syndrome; GABA(A) receptor; Gaboxadol; Ganaxolone; Targeted treatment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiopathology
  • Clinical Trials as Topic
  • Disease Models, Animal
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology*
  • GABA Modulators / therapeutic use
  • Humans
  • Pregnanolone / analogs & derivatives
  • Pregnanolone / therapeutic use
  • Receptors, GABA-A / metabolism*


  • GABA Modulators
  • Receptors, GABA-A
  • ganaxolone
  • Pregnanolone