Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science Signaling (Impact Factor: 6.28). 02/2008; 1(5):pe6. DOI: 10.1126/stke.15pe6
Source: PubMed


Fragile X syndrome (FXS) mental retardation is caused by loss-of-function mutations in an RNA-binding protein, fragile X mental retardation protein (FMRP). Previous studies in patients or animal models of FXS have identified alterations in dendritic spine structure, as well as synaptic plasticity induced by metabotropic glutamate receptors (mGluRs). The translation of multiple messenger RNA (mRNA) targets of FMRP is regulated by mGluRs at synapses. Here, we incorporate data from several studies into a working model of how FMRP regulates mGluR-stimulated protein synthesis and, in turn, regulates protein synthesis-dependent synaptic plasticity. Understanding the complex functions of FMRP at the synapse will lead to a better understanding of the neurobiological underpinnings of mental retardation.

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    • "FMRP is 70-80 KDa protein abundantly expressed in brain and testis [13] [14]. FMRP-mediated translational regulation plays important roles in proper synaptic connectivity [15] and plasticity [16] [17]. Since, the dendritic protein synthesis is under the strict control for the achieving synaptic plasticity [18] [19], any change in the level of FMRP may lead to alterations in synaptic plasticity and thus learning and memory. "
    Dataset: 347978.v1

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    • "The expression of APP can be upregulated upon mGluR5 stimulation. FMRP, which is also regulated by mGluR5 (Ronesi and Huber, 2008; Wang et al., 2008a; Wang and Zhuo, 2012), binds to and represses the translation of APP mRNA due to mGluR5 activation (Westmark and Malter, 2007; Westmark, 2013). The mGluR5 links FMRP with APP. "

    Frontiers in Cellular Neuroscience 02/2015; 9:43. DOI:10.3389/fncel.2015.00043 · 4.29 Impact Factor
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    • "One potential mechanism, coined the metabotropic glutamate receptor (mGluR) theory of FXS, was proposed following observations linking mGluR signaling, long-term depression (LTD), protein synthesis, and FMRP function (Weiler et al., 1997; Huber et al., 2000, 2001, 2002) and has been a focus of recent basic and clinical research (Bear et al., 2004; Dölen et al., 2007; Ronesi and Huber, 2008; Berry-Kravis, 2014). At the time of writing, drugs targeting several molecular players in the mGluR signaling pathway are being studied in clinical trials (Berry-Kravis, 2014; Erickson et al., 2014; Jacquemont et al., 2014; Pop et al., 2014). "
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    ABSTRACT: A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.
    Frontiers in Genetics 07/2014; 5:239. DOI:10.3389/fgene.2014.00239
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