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

Franklin, Aimee V.; King, Margaret K.; Palomo, Valle; Martı́nez, Ana; McMahon, Lori L.; Jope, Richard S.

doi:10.1016/j.biopsych.2013.08.003

Cited by 102 publications

(139 citation statements)

References 75 publications

(96 reference statements)

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“…For a more extensive review of Fmr1 knockout mice behavioral phenotypes see [180]. Behavior: social dominance [119]; sociability [132] Cognition: object recognition (chronic, not acute) [121]; fear conditioning [120]; associative motor learning (acute) [133]; inhibitory avoidance (chronic and acute) [129,133]; extinction memory (chronic) [129] LTP deficits in the amygdala and hippocampus (bath application) [128,134]; LTD (bath application) [135] startle response, † rotarod performance [131]; object recognition (acute) [121,134]; coordinate and categorical tasks (acute) [134]; analgesic response [121] mGlu5 NAMs used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• lithium [113,122,123,134,[153][154][155] specific GSK3β antagonists [122,134] PAK Genetic (dn) Cellular: dendritic spine density (partially) [156] N/A N/A Shown are genetic and pharmacological rescue strategies and their effects in Fmr1 knockout mice. The following strategies were confirmed in studies using Drosophila models of fragile X syndrome (FXS): metabotropic glutamate receptor (mGluR) [167], gamma-aminobutyric acid (GABA) [168] (but see [169]), lithium [167], minocycline [170], phosphodiesterase-4 (PDE-4) [ A recent study suggested that simultaneous stimulation of D1R and serotonin (5HT) receptors rescued impaired synaptic AMPA receptor insertion and plasticity, and improved fear conditioning and Y maze learning deficits [115].…”

Section: Macro-orchidismmentioning

confidence: 99%

“…Moreover, lithium, an antagonist of GSK3β, is already approved for use in humans, and p110β-selective inhibitors have been developed for cancer research. While mouse studies with lithium and a specific GSK3β antagonist already show promising effects on behavior and cognition in FXS mice [122,123,134,155], so far, p110β-selective inhibitors have only been validated in vitro in mice and in vivo in patient-derived cell lines [64,66].…”

Section: Manipulating Specific Targets Of Fmrpmentioning

confidence: 99%

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Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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Section: Macro-orchidismmentioning

confidence: 99%

Section: Macro-orchidismmentioning

confidence: 99%

Section: Macro-orchidismmentioning

confidence: 99%

Section: Manipulating Specific Targets Of Fmrpmentioning

confidence: 99%

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Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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“…A major finding in brain samples of Fmr1 -/-mice is the abnormally high levels of GSK3b, a key kinase shown to play critical roles in several molecular pathways, including MAPK, Cyclin, Akt, and the canonical Wnt/b-catenin signaling pathway [26,[45][46][47]. The role of GSK3b, as part of the canonical Wnt/bcatenin signaling pathway, was shown to be important during adult neurogenesis in the murine hippocampus [29] and in FXS pathology in Fmr1 -/-mice [27,28].…”

Section: Expression Of Gsk3b and B-catenin In Fx-hnpcsmentioning

confidence: 99%

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Telias

Mayshar

Amit

et al. 2015

Stem Cells and Development

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Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment. It is caused by developmental inactivation of the FMR1 gene and the absence of its encoded protein FMRP, which plays pivotal roles in brain development and function. In FXS embryos with full FMR1 mutation, FMRP is expressed during early embryogenesis and is gradually downregulated at the third trimester of pregnancy. FX-human embryonic stem cells (FX-hESCs), derived from FX human blastocysts, demonstrate the same pattern of developmentally regulated FMR1 inactivation when subjected to in vitro neural differentiation (IVND). In this study, we used this in vitro human platform to explore the molecular mechanisms downstream to FMRP in the context of early human embryonic neurogenesis. Our results show a novel role for the SOX superfamily of transcription factors, specifically for SOX2 and SOX9, which could explain the reduced and delayed neurogenesis observed in FX cells. In addition, we assess in this study the ''GSK3b theory of FXS'' for the first time in a human-based model. We found no evidence for a pathological increase in GSK3b protein levels upon cellular loss of FMRP, in contrast to what was found in the brain of Fmr1 knockout mice. Our study adds novel data on potential downstream targets of FMRP and highlights the importance of the FX-hESC IVND system.

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Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome

Jawaid

Kidd

Wang

et al. 2017

Glia

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Fragile X Syndrome (FXS) is the major cause of inherited mental retardation and the leading genetic cause of Autism spectrum disorders. FXS is caused by mutations in the Fragile X Mental Retardation 1 (Fmr1) gene, which results in transcriptional silencing of Fragile X Mental Retardation Protein (FMRP). To elucidate cellular mechanisms involved in the pathogenesis of FXS, we compared dendritic spines in the hippocampal CA1 region of adult wild-type (WT) and Fmr1 knockout (Fmr1-KO) mice. Using diolistic labeling, confocal microscopy, and three-dimensional electron microscopy, we show a significant increase in the diameter of secondary dendrites, an increase in dendritic spine density, and a decrease in mature dendritic spines in adult Fmr1-KO mice. While WT and Fmr1-KO mice had the same mean density of spines, the variance in spine density was three times greater in Fmr1-KO mice. Reduced astrocyte participation in the tripartite synapse and less mature post-synaptic densities were also found in Fmr1-KO mice. We investigated whether the increase in synaptic spine density was associated with altered synaptic pruning during development. Our data are consistent with reduced microglia-mediated synaptic pruning in the CA1 region of Fmr1-KO hippocampi when compared with WT littermates at postnatal day 21, which is the peak period of synaptic pruning in the mouse hippocampus. Collectively, these results support abnormal synaptogenesis and synaptic remodeling in mice deficient in FMRP. Deficits in the maturation and distribution of synaptic spines on dendrites of CA1 hippocampal neurons may play a role in the intellectual disabilities associated with FXS.

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

Cited by 102 publications

References 75 publications

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

Alterations in CA1 hippocampal synapses in a mouse model of fragile X syndrome

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