Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Chen, Tao; Lu, Jing-Shan; Song, Qi; Liu, Ming-Gang; Koga, Katsumi; Descalzi, Giannina; Li, Yunqing; Zhuo, Min

doi:10.1038/npp.2014.44

Cited by 51 publications

(90 citation statements)

References 68 publications

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“…The ERK/MAPK and mTOR pathways are two critical signaling pathways that regulate protein synthesis in the brain and have been implicated in the pathophysiology of fragile X (3,4). We focused on the neocortex, because neocortical network activity is enhanced in fragile X (20), and proteinsynthesis-dependent synaptic plasticity is impaired in the fragile X cortex (21). ERK/MAPK signaling is initiated by activation of Ras, which phosphorylates the protein kinase MEK.…”

Section: Erk But Not Mtor Signaling Is Elevated In the Cortex Of Fmr1 Komentioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.F ragile X syndrome (FXS) is the most common heritable form of intellectual disability and a leading genetic cause of autism. Individuals with FXS typically suffer from a range of cognitive and behavioral deficits that can include anxiety, stereotypic movements, hyperactivity, seizures, and aggression, as well as social deficits typical of autism (1). FXS is caused by transcriptional silencing or mutation of the FMR1 gene encoding the RNA-binding protein, FMRP (fragile X mental retardation protein). FMRP binds to >1,000 mRNAs, including transcripts encoding both preand postsynaptic proteins important for synaptic function, and represses their translation via ribosome stalling (2). Loss of FMRP expression in fragile X syndrome would be expected to cause translational derepression of these target mRNAs.FMRP is strategically localized to dendrites, dendritic spines, axons, and cell bodies to control protein synthesis. Loss of FMRP causes enhanced protein synthesis, which can lead to altered spine morphology, synaptic circuits, and synaptic function with robust effects on higher cognitive function. The excessive, unchecked protein synthesis and impaired stimulus-induced protein synthesis are considered to be major contributors to the pathophysiology of fragile X (3-5). Increased protein synthesis has been demonstrated in whole-animal st...

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Section: Erk But Not Mtor Signaling Is Elevated In the Cortex Of Fmr1 Komentioning

confidence: 99%

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Sawicka

Pyronneau

Chao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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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“…While altered hippocampal long-term potentiation (LTP) is not typical in Fmr1 KO mice (Godfraind et al, 1996), when it is observed the deficit is in LTP stability (Lauterborn et al, 2007). Reduced or abolished LTP is observed in neocortex and amygdala (Larson et al, 2005; Zhao et al, 2005; Shang et al, 2009; Chen et al, 2014). However, the functional changes that link dysregulated translation to impaired cognition are unknown, and a theory is lacking.…”

Section: Introductionmentioning

confidence: 99%

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

Radwan

Dvořák

Fenton

2016

Neurobiology of Disease

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Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). Absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta-gamma phase-amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions.

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Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Cited by 51 publications

References 68 publications

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice

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

Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

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