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Glycogen Synthase Kinase-3 Inhibitors Reverse Deficits in Long-term Potentiation and Cognition in Fragile X Mice

Published:September 16, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.08.003

      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.

      Key Words

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      References

        • Garber K.
        • Smith K.T.
        • Reines D.
        • Warren S.T.
        Transcription, translation and fragile X syndrome.
        Curr Opin Genet Dev. 2006; 16: 270-275
        • Bhakar A.L.
        • Dolen G.
        • Bear M.F.
        The pathophysiology of fragile X (and what it teaches us about synapses).
        Annu Rev Neurosci. 2012; 35: 417-443
        • Ornstein P.A.
        • Schaaf J.M.
        • Hooper S.R.
        • Hatton D.D.
        • Mirrett P.
        • Bailey Jr., D.B.
        Memory skills of boys with fragile X syndrome.
        Am J Ment Retard. 2008; 113: 453-465
        • Dissanayake C.
        • Bui Q.
        • Bulhak-Paterson D.
        • Huggins R.
        • Loesch D.Z.
        Behavioural and cognitive phenotypes in idiopathic autism versus autism associated with fragile X syndrome.
        J Child Psychol Psychiatry. 2009; 50: 290-299
        • Errijgers V.
        • Kooy R.F.
        Genetic modifiers in mice: The example of the fragile X mouse model.
        Cytogenet Genome Res. 2004; 105: 448-454
        • Hernandez R.N.
        • Feinberg R.L.
        • Vaurio R.
        • Passanante N.M.
        • Thompson R.E.
        • Kaufmann W.E.
        Autism spectrum disorder in fragile X syndrome: A longitudinal evaluation.
        Am J Med Genet A. 2009; 149A: 1125-1137
        • Bagni C.
        • Tassone F.
        • Neri G.
        • Hagerman R.
        Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics.
        J Clin Invest. 2012; 122: 4314-4322
        • Hagerman R.
        • Lauterborn J.
        • Au J.
        • Berry-Kravis E.
        Fragile X syndrome and targeted treatment trials.
        Results Probl Cell Differ. 2012; 54: 297-335
        • Jacquemont S.
        • Curie A.
        • des Portes V.
        • Torrioli M.G.
        • Berry-Kravis E.
        • Hagerman R.J.
        • et al.
        Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056.
        Sci Transl Med. 2011; 3 (64ra61)
        • Berry-Kravis E.M.
        • Hessl D.
        • Rathmell B.
        • Zarevics P.
        • Cherubini M.
        • Walton-Bowen K.
        • et al.
        Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: A randomized, controlled, phase 2 trial.
        Sci Transl Med. 2012; 4 (152ra127)
        • Bakker D.B.
        Fmr1 knockout mice: A model to study fragile X mental retardation. The Dutch-Belgian Fragile X Consortium.
        Cell. 1994; 78: 23-33
        • Gross C.
        • Berry-Kravis E.M.
        • Bassell G.J.
        Therapeutic strategies in fragile X syndrome: Dysregulated mGluR signaling and beyond.
        Neuropsychopharmacology. 2012; 37: 178-195
        • Godfraind J.M.
        • Reyniers E.
        • De Boulle K.
        • D’Hooge R.
        • De Deyn P.P.
        • Bakker C.E.
        • et al.
        Long-term potentiation in the hippocampus of fragile X knockout mice.
        Am J Med Genet. 1996; 64: 246-251
        • Huber K.M.
        • Gallagher S.M.
        • Warren S.T.
        • Bear M.F.
        Altered synaptic plasticity in a mouse model of fragile X mental retardation.
        Proc Natl Acad Sci U S A. 2002; 99: 7746-7750
        • Bear M.F.
        • Huber K.M.
        • Warren S.T.
        The mGluR theory of fragile X mental retardation.
        Trends Neurosci. 2004; 27: 370-377
        • Dolen G.
        • Bear M.F.
        Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome.
        J Physiol. 2008; 586: 1503-1508
        • Michalon A.
        • Sidorov M.
        • Ballard T.M.
        • Ozmen L.
        • Spooren W.
        • Wettstein J.G.
        • et al.
        Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
        Neuron. 2012; 74: 49-56
        • Eadie B.D.
        • Cushman J.
        • Kannangara T.S.
        • Fanselow M.S.
        • Christie B.R.
        NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice.
        Hippocampus. 2012; 22: 241-254
        • Yun S.H.
        • Trommer B.L.
        Fragile X mice: Reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus.
        J Neurosci Res. 2011; 89: 176-182
        • McHugh T.J.
        • Jones M.W.
        • Quinn J.J.
        • Balthasar N.
        • Coppari R.
        • Elmquist J.K.
        • et al.
        Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network.
        Science. 2007; 317: 94-99
        • Yuskaitis C.J.
        • Mines M.A.
        • King M.K.
        • Sweatt J.D.
        • Miller C.A.
        • Jope R.S.
        Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.
        Biochem Pharmacol. 2010; 79: 632-646
        • Liu Z.H.
        • Chuang D.M.
        • Smith C.B.
        Lithium ameliorates phenotypic deficits in a mouse model of fragile X syndrome.
        Int J Neuropsychopharmacol. 2011; 14: 618-630
        • Choi C.H.
        • Schoenfeld B.P.
        • Bell A.J.
        • Hinchey P.
        • Kollaros M.
        • Gertner M.J.
        • et al.
        Pharmacological reversal of synaptic plasticity deficits in the mouse model of Fragile X syndrome by group II mGluR antagonist or lithium treatment.
        Brain Res. 2011; 1380: 106-119
        • Berry-Kravis E.
        • Sumis A.
        • Hervey C.
        • Nelson M.
        • Porges S.W.
        • Weng N.
        • et al.
        Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome.
        J Dev Behav Pediatr. 2008; 29: 293-302
        • McBride S.M.
        • Choi C.H.
        • Wang Y.
        • Liebelt D.
        • Braunstein E.
        • Ferreiro D.
        • et al.
        Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome.
        Neuron. 2005; 45: 753-764
        • Jope R.S.
        Glycogen synthase kinase-3 in the etiology and treatment of mood disorders.
        Front Mol Neurosci. 2011; 4: 16
        • Jope R.S.
        • Johnson G.V.
        The glamour and gloom of glycogen synthase kinase-3.
        Trends Biochem Sci. 2004; 29: 95-102
        • Min W.W.
        • Yuskaitis C.J.
        • Yan Q.
        • Sikorski C.
        • Chen S.
        • Jope R.S.
        • et al.
        Elevated glycogen synthase kinase-3 activity in Fragile X mice: Key metabolic regulator with evidence for treatment potential.
        Neuropharmacology. 2009; 56: 463-472
        • Peineau S.
        • Taghibiglou C.
        • Bradley C.
        • Wong T.P.
        • Liu L.
        • Lu J.
        • et al.
        LTP inhibits LTD in the hippocampus via regulation of GSK3beta.
        Neuron. 2007; 53: 703-717
        • Hooper C.
        • Markevich V.
        • Plattner F.
        • Killick R.
        • Schofield E.
        • Engel T.
        • et al.
        Glycogen synthase kinase-3 inhibition is integral to long-term potentiation.
        Eur J Neurosci. 2007; 25: 81-86
        • Zhu L.Q.
        • Wang S.H.
        • Liu D.
        • Yin Y.Y.
        • Tian Q.
        • Wang X.C.
        • et al.
        Activation of glycogen synthase kinase-3 inhibits long-term potentiation with synapse-associated impairments.
        J Neurosci. 2007; 27: 12211-12220
        • Hallett P.J.
        • Collins T.L.
        • Standaert D.G.
        • Dunah A.W.
        Biochemical fractionation of brain tissue for studies of receptor distribution and trafficking.
        Curr Protoc Neurosci. 2008; (Chapter 1:Unit 1.16)
        • Hunsaker M.R.
        • Kim K.
        • Willemsen R.
        • Berman R.F.
        CGG trinucleotide repeat length modulates neural plasticity and spatiotemporal processing in a mouse model of the fragile X premutation.
        Hippocampus. 2012; 22: 2260-2275
        • Bain J.
        • Plater L.
        • Elliott M.
        • Shpiro N.
        • Hastie C.J.
        • McLauchlan H.
        • et al.
        The selectivity of protein kinase inhibitors: A further update.
        Biochem J. 2007; 408: 297-315
        • Dobrunz L.E.
        • Stevens C.F.
        Heterogeneity of release probability, facilitation, and depletion at central synapses.
        Neuron. 1997; 18: 995-1008
        • Ventura R.
        • Pascucci T.
        • Catania M.V.
        • Musumeci S.A.
        • Puglisi-Allegra S.
        Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: Involvement of dopamine in the medial prefrontal cortex.
        Behav Pharmacol. 2004; 15: 433-442
        • Pacey L.K.
        • Doss L.
        • Cifelli C.
        • van der Kooy D.
        • Heximer S.P.
        • Hampson D.R.
        Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse.
        Mol Cell Neurosci. 2011; 46: 563-572
        • Bhattacharya A.
        • Klann E.
        Fragile X syndrome therapeutics S(C)TEP through the developmental window.
        Neuron. 2012; 74: 1-3
        • Hunsaker M.R.
        • Kesner R.P.
        Evaluating the differential roles of the dorsal dentate gyrus, dorsal CA3, and dorsal CA1 during a temporal ordering for spatial locations task.
        Hippocampus. 2008; 18: 955-964
        • Goodrich-Hunsaker N.J.
        • Hunsaker M.R.
        • Kesner R.P.
        The interactions and dissociations of the dorsal hippocampus subregions: How the dentate gyrus, CA3, and CA1 process spatial information.
        Behav Neurosci. 2008; 122: 16-26
        • Hunsaker M.R.
        • Rosenberg J.S.
        • Kesner R.P.
        The role of the dentate gyrus, CA3a,b, and CA3c for detecting spatial and environmental novelty.
        Hippocampus. 2008; 18: 1064-1073
        • Martinez A.
        • Alonso M.
        • Castro A.
        • Perez C.
        • Moreno F.J.
        First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: Thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease.
        J Med Chem. 2002; 45: 1292-1299
        • Palomo V.
        • Soteras I.
        • Perez D.I.
        • Perez C.
        • Gil C.
        • Campillo N.E.
        • et al.
        Exploring the binding sites of glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities.
        J Med Chem. 2011; 54: 8461-8470
        • Goodrich-Hunsaker N.J.
        • Hunsaker M.R.
        • Kesner R.P.
        Dissociating the role of the parietal cortex and dorsal hippocampus for spatial information processing.
        Behav Neurosci. 2005; 119: 1307-1315
        • Honey R.C.
        • Watt A.
        • Good M.
        Hippocampal lesions disrupt an associative mismatch process.
        J Neurosci. 1998; 18: 2226-2230
        • Wallenstein G.V.
        • Eichenbaum H.
        • Hasselmo M.E.
        The hippocampus as an associator of discontiguous events.
        Trends Neurosci. 1998; 21: 317-323
        • Rolls E.T.
        • Kesner R.P.
        A computational theory of hippocampal function, and empirical tests of the theory.
        Prog Neurobiol. 2006; 79: 1-48
        • Hoge J.
        • Kesner R.P.
        Role of CA3 and CA1 subregions of the dorsal hippocampus on temporal processing of objects.
        Neurobiol Learn Mem. 2007; 88: 225-231
        • Hunsaker M.R.
        • Kesner R.P.
        The operation of pattern separation and pattern completion processes associated with different attributes or domains of memory.
        Neurosci Biobehav Rev. 2013; 37: 36-58
        • Dolen G.
        • Osterweil E.
        • Rao B.S.
        • Smith G.B.
        • Auerbach B.D.
        • Chattarji S.
        • et al.
        Correction of fragile X syndrome in mice.
        Neuron. 2007; 56: 955-962
        • Kooy R.F.
        • D’Hooge R.
        • Reyniers E.
        • Bakker C.E.
        • Nagels G.
        • De Boulle K.
        • et al.
        Transgenic mouse model for the fragile X syndrome.
        Am J Med Genet. 1996; 64: 241-245
        • D’Hooge R.
        • Nagels G.
        • Franck F.
        • Bakker C.E.
        • Reyniers E.
        • Storm K.
        • et al.
        Mildly impaired water maze performance in male Fmr1 knockout mice.
        Neuroscience. 1997; 76: 367-376
        • Fisch G.S.
        • Hao H.K.
        • Bakker C.
        • Oostra B.A.
        Learning and memory in the FMR1 knockout mouse.
        Am J Med Genet. 1999; 84: 277-282
        • Paradee W.
        • Melikian H.E.
        • Rasmussen D.L.
        • Kenneson A.
        • Conn P.J.
        • Warren S.T.
        Fragile X mouse: Strain effects of knockout phenotype and evidence suggesting deficient amygdala function.
        Neuroscience. 1999; 94: 185-192
        • Peier A.M.
        • McIlwain K.L.
        • Kenneson A.
        • Warren S.T.
        • Paylor R.
        • Nelson D.L.
        (Over)correction of FMR1 deficiency with YAC transgenics: Behavioral and physical features.
        Hum Mol Genet. 2000; 9: 1145-1159
        • Dobkin C.
        • Rabe A.
        • Dumas R.
        • El Idrissi A.
        • Haubenstock H.
        • Brown W.T.
        Fmr1 knockout mouse has a distinctive strain-specific learning impairment.
        Neuroscience. 2000; 100: 423-429
        • Mineur Y.S.
        • Sluyter F.
        • de Wit S.
        • Oostra B.A.
        • Crusio W.E.
        Behavioral and neuroanatomical characterization of the Fmr1 knockout mouse.
        Hippocampus. 2002; 12: 39-46
        • Yan Q.J.
        • Asafo-Adjei P.K.
        • Arnold H.M.
        • Brown R.E.
        • Bauchwitz R.P.
        A phenotypic and molecular characterization of the fmr1-tm1Cgr fragile X mouse.
        Genes Brain Behav. 2004; 3: 337-359
        • Baker K.B.
        • Wray S.P.
        • Ritter R.
        • Mason S.
        • Lanthorn T.H.
        • Savelieva K.V.
        Male and female Fmr1 knockout mice on C57 albino background exhibit spatial learning and memory impairments.
        Genes Brain Behav. 2010; 9: 562-574
        • Bliss T.V.
        • Collingridge G.L.
        A synaptic model of memory: Long-term potentiation in the hippocampus.
        Nature. 1993; 361: 31-39
        • Mines M.A.
        • Jope R.S.
        Glycogen synthase kinase-3: A promising therapeutic target for fragile X syndrome.
        Front Mol Neurosci. 2011; 4: 35
        • Mines M.A.
        • Yuskaitis C.J.
        • King M.K.
        • Beurel E.
        • Jope R.S.
        GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism.
        PLoS One. 2010; 5: e9706
        • Yuskaitis C.J.
        • Beurel E.
        • Jope R.S.
        Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome.
        Biochim Biophys Acta. 2010; 1802: 1006-1012
        • Liu Z.H.
        • Huang T.
        • Smith C.B.
        Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome.
        Neurobiol Dis. 2012; 45: 1145-1152
        • Guo W.
        • Murthy A.C.
        • Zhang L.
        • Johnson E.B.
        • Schaller E.G.
        • Allan A.M.
        • et al.
        Inhibition of GSK3beta improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome.
        Hum Mol Genet. 2012; 21: 681-691
        • Vrij F.M.
        • Levenga J.
        • van der Linde H.C.
        • Koekkoek S.K.
        • De Zeeuw C.I.
        • Nelson D.L.
        • et al.
        Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice.
        Neurobiol Dis. 2008; 31 (de): 127-132
        • Suvrathan A.
        • Hoeffer C.A.
        • Wong H.
        • Klann E.
        • Chattarji S.
        Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome.
        Proc Natl Acad Sci U S A. 2010; 107: 11591-11596
        • Gross C.
        • Berry-Kravis E.M.
        • Bassell G.J.
        Therapeutic strategies in fragile X syndrome: Dysregulated mGluR signaling and beyond.
        Neuropsychopharmacology. 2011; 37: 178-195
        • Thomas A.M.
        • Bui N.
        • Perkins J.R.
        • Yuva-Paylor L.A.
        • Paylor R.
        Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome.
        Psychopharmacology (Berl). 2012; 219: 47-58
        • Busquets-Garcia A.
        • Gomis-Gonzalez M.
        • Guegan T.
        • Agustin-Pavon C.
        • Pastor A.
        • Mato S.
        • et al.
        Targeting the endocannabinoid system in the treatment of fragile X syndrome.
        Nat Med. 2013; 19: 603-607
        • Chen P.
        • Gu Z.
        • Liu W.
        • Yan Z.
        Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons.
        Mol Pharmacol. 2007; 72: 40-51
        • Wei J.
        • Liu W.
        • Yan Z.
        Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3.
        J Biol Chem. 2010; 285: 26369-26376
        • Bradley C.A.
        • Peineau S.
        • Taghibiglou C.
        • Nicolas C.S.
        • Whitcomb D.J.
        • Bortolotto Z.A.
        • et al.
        A pivotal role of GSK-3 in synaptic plasticity.
        Front Mol Neurosci. 2012; 5: 13
        • Gatto C.L.
        • Broadie K.
        The fragile X mental retardation protein in circadian rhythmicity and memory consolidation.
        Mol Neurobiol. 2009; 39: 107-129
        • Kemper M.B.
        • Hagerman R.J.
        • Altshul-Stark D.
        Cognitive profiles of boys with the fragile X syndrome.
        Am J Med Genet. 1988; 30: 191-200
        • Cornish K.M.
        • Munir F.
        • Cross G.
        Spatial cognition in males with fragile-X syndrome: Evidence for a neuropsychological phenotype.
        Cortex. 1999; 35: 263-271
        • Cornish K.
        • Munir F.
        • Wilding J.
        A neuropsychological and behavioural profile of attention deficits in fragile X syndrome [in Spanish].
        Rev Neurol. 2001; 33: S24-S29
        • Guo W.
        • Allan A.M.
        • Zong R.
        • Zhang L.
        • Johnson E.B.
        • Schaller E.G.
        • et al.
        Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning.
        Nat Med. 2011; 17: 559-565

      Linked Article

      • (Li+)ghting the Way for a Treatment for Cognitive Impairments in Fragile X Syndrome
        Biological PsychiatryVol. 75Issue 3
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          Basic research on fragile X syndrome (FXS) is currently entering its third decade. A wealth of knowledge has been generated concerning the pathophysiology of FXS that has fueled new treatment strategies. As often happens in any field of biology, some theories gain more ground than others, which languish many years before an important study brings it back into the limelight. The most intensely studied theory in FXS research is the “mGluR theory of FXS” (1), which posits that excessive group I metabotropic glutamate receptor (mGluR1/5)–mediated translation in neurons is responsible for most synaptic and behavioral abnormalities associated with the syndrome.
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