Inhibition of GSK3β improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome

Hum Mol Genet. 2012 Feb 1;21(3):681-91. doi: 10.1093/hmg/ddr501. Epub 2011 Nov 2.


Fragile X syndrome (FXS), a common inherited form of intellectual disability with learning deficits, results from a loss of fragile X mental retardation protein (FMRP). Despite extensive research, treatment options for FXS remain limited. Since FMRP is known to play an important role in adult hippocampal neurogenesis and hippocampus-dependent learning and FMRP regulates the adult neural stem cell fate through the translational regulation of glycogen synthase kinase 3β (GSK3β), we investigated the effects of a GSK3β inhibitor, SB216763, on Fmr1 knockout mice (Fmr1 KO). We found that the inhibition of GSK3β could reverse the hippocampus-dependent learning deficits and rescue adult hippocampal neurogenesis at multiple stages in Fmr1 KO mice. Our results point to GSK3β inhibition as a potential treatment for the learning deficits seen in FXS.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / enzymology*
  • Fragile X Syndrome / pathology
  • Fragile X Syndrome / physiopathology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / drug effects*
  • Hippocampus / physiopathology
  • Indoles / pharmacology*
  • Learning / drug effects*
  • Male
  • Maleimides / pharmacology*
  • Mice
  • Mice, Knockout
  • Nerve Net
  • Neurogenesis / drug effects*
  • Neurons / drug effects
  • Neurons / ultrastructure
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*


  • Fmr1 protein, mouse
  • Indoles
  • Maleimides
  • Protein Kinase Inhibitors
  • SB 216763
  • Fragile X Mental Retardation Protein
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3