title: Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice.
abstract: 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.
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Aimee V
authors.initials: AV
authors.lastname: Franklin
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Margaret K
authors.initials: MK
authors.lastname: King
authors.affiliation: Instituto Quimica Medica-Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.affiliation: Instituto Quimica Medica-Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Lori L
authors.initials: LL
authors.lastname: McMahon
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, and Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida. Electronic address: rjope@med.miami.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000473:pathology
chemical_list: D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D051860:Fragile X Messenger Ribonucleoprotein 1; D038362:Glycogen Synthase Kinase 3; D051528:Guanylate Kinases; D018021:Lithium Chloride; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; C501447:Dlg4 protein, mouse
keywords: Cognition; fragile X syndrome; glycogen synthase kinase-3; learning; long-term potentiation (LTP); synaptic plasticity
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