Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome

Muddashetty, Ravi; Kelić, S.; Groß, Christina; Xu, Mei; Bassell, Gary J.

doi:10.1523/jneurosci.0937-07.2007

Cited by 379 publications

(473 citation statements)

References 64 publications

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“…The dendritic trafficking of this transcript and the role of local translated CaMKIIa in synaptic plasticity events has been widely studied (Mayford et al, 1996;Miller et al, 2002;Ouyang et al, 1999). Other relatively abundant mRNAs in the neuropil region included the transcripts encoding for Shank1, PSD95 (postsynaptic density protein 95), Dendrin and MAP (microtubule-associated protein) 1A (Cajigas et al, 2012), all of them previously reported as dendritic mRNAs (Bockers et al, 2004;Herb et al, 1997;Muddashetty et al, 2007;Tucker et al, 1989).…”

Section: Cis-acting Elements and Mrna Transport Into Dendritesmentioning

confidence: 99%

BDNF-induced local protein synthesis and synaptic plasticity

2014

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a b s t r a c tBrain-derived neurotrophic factor (BDNF) is an important regulator of synaptic transmission and longterm potentiation (LTP) in the hippocampus and in other brain regions, playing a role in the formation of certain forms of memory. The effects of BDNF in LTP are mediated by TrkB (tropomyosin-related kinase B) receptors, which are known to be coupled to the activation of the Ras/ERK, phosphatidylinositol 3-kinase/Akt and phospholipase C-g (PLC-g) pathways. The role of BDNF in LTP is best studied in the hippocampus, where the neurotrophin acts at pre-and post-synaptic levels. Recent studies have shown that BDNF regulates the transport of mRNAs along dendrites and their translation at the synapse, by modulating the initiation and elongation phases of protein synthesis, and by acting on specific miRNAs. Furthermore, the effect of BDNF on transcription regulation may further contribute to long-term changes in the synaptic proteome. In this review we discuss the recent progress in understanding the mechanisms contributing to the short-and long-term regulation of the synaptic proteome by BDNF, and the role in synaptic plasticity, which is likely to influence learning and memory formation.This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

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Section: Cis-acting Elements and Mrna Transport Into Dendritesmentioning

confidence: 99%

BDNF-induced local protein synthesis and synaptic plasticity

2014

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“…FMRP is an mRNA-binding protein that plays a role in various aspects of activity-dependent mRNA metabolism in neurons, such as mRNA transport (Dictenberg et al, 2008;Estes et al, 2008), stability (Zalfa et al, 2007), and regulation of mRNA translation (see, eg, Zalfa et al, 2003;Muddashetty et al, 2007;Bechara et al, 2009). Here, we will focus on the role of FMRP in translational control, as this is the so far best-studied function of FMRP in RNA metabolism.…”

Section: Fmrp: a Key Regulator Of Neuronal Functionmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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“…The translation of these mRNAs at post-synaptic dendrites stimulates the internalization of surface expressed AMPA and NMDA receptors. In the absence of FMRP, an increase in the translation of target mRNA occurs in vivo (Zalfa et al, 2003;Lu et al, 2004;Muddashetty et al, 2007). Thus, exaggerated LTD in The culmination of data that implicated exaggerated mGluR signalling in the phenotypical profile of Fmr1 knockout mice became known as the 'mGluR theory of fragile X' (Huber et al, 2002).…”

Section: The Mouse Model and Molecular Mechanisms Of Fragile X Syndromementioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome

Cited by 379 publications

References 64 publications

BDNF-induced local protein synthesis and synaptic plasticity

BDNF-induced local protein synthesis and synaptic plasticity

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

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