Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice

Biol Psychiatry. 2014 Feb 1;75(3):198-206. doi: 10.1016/j.biopsych.2013.08.003. Epub 2013 Sep 13.


Background: Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes.

Methods: We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor-dependent long-term potentiation at medial perforant path synapses onto dentate granule cells and dentate gyrus-dependent cognitive behavioral tasks.

Results: GSK3 inhibitors completely rescued deficits in long-term potentiation at medial perforant path-dentate granule cells synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent cognitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects.

Conclusions: These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.

Keywords: Cognition; fragile X syndrome; glycogen synthase kinase-3; learning; long-term potentiation (LTP); synaptic plasticity.

Publication types

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

MeSH terms

  • Animals
  • Cognition / drug effects*
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein
  • Electric Stimulation
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Syndrome / complications*
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / pathology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Guanylate Kinases / metabolism
  • Hippocampus / pathology
  • In Vitro Techniques
  • Lithium Chloride / pharmacology
  • Lithium Chloride / therapeutic use
  • Long-Term Potentiation / drug effects*
  • Long-Term Potentiation / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Synapses / drug effects
  • Synapses / genetics
  • Synapses / pathology


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Excitatory Amino Acid Antagonists
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • Fragile X Mental Retardation Protein
  • Glycogen Synthase Kinase 3
  • Guanylate Kinases
  • Lithium Chloride