The Pathophysiology of Fragile X (and What It Teaches Us about Synapses)

Howard Hughes Medical Institute, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Annual Review of Neuroscience (Impact Factor: 19.32). 04/2012; 35(1):417-43. DOI: 10.1146/annurev-neuro-060909-153138
Source: PubMed


Fragile X is the most common known inherited cause of intellectual disability and autism, and it typically results from transcriptional silencing of FMR1 and loss of the encoded protein, FMRP (fragile X mental retardation protein). FMRP is an mRNA-binding protein that functions at many synapses to inhibit local translation stimulated by metabotropic glutamate receptors (mGluRs) 1 and 5. Recent studies on the biology of FMRP and the signaling pathways downstream of mGluR1/5 have yielded deeper insight into how synaptic protein synthesis and plasticity are regulated by experience. This new knowledge has also suggested ways that altered signaling and synaptic function can be corrected in fragile X, and human clinical trials based on this information are under way.

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    • " and in a mouse model for the disease there are more immature spines in hippocampus and neocortex , and the total number of dendritic spines is increased ( Levenga and Willemsen , 2012 ) . A large variety of changes in synaptic transmission have been observed in the mouse model for FXS , including changes in short - and in long - term plasticity ( Bhakar et al . , 2012 ) . Most of them are thought to be secondary to the effects of FMRP on translation , but some of them are caused by a direct binding of FMRP to proteins involved in synaptic transmission ( Brager and Johnston , 2014 ) . Neurofibromatosis type 1 is caused by heterozygous mutations in the Nf1 gene . Nf1 encodes the protein neurofibromin ,"
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    ABSTRACT: Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.
    Frontiers in Cellular Neuroscience 07/2015; 9:234. DOI:10.3389/fncel.2015.00234 · 4.29 Impact Factor
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    • "The pharmacotherapy for fragile X and Rett syndromes is the focus of this research topic. The metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential target for treating fragile X syndrome (Bhakar et al., 2012; Wang and Zhuo, 2012; Scharf et al., 2015). Gandhi et al. report that mGluR5 antagonist MPEP reverses maze learning and PSD-95 deficits in fragile X mice (Gandhi et al., 2014). "
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    ABSTRACT: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired social communication, abnormal language development, restricted interests, and repetitive and stereotyped behaviors. Investigation of cellular and synaptic deficits in ASDs will provide further insights into the pathogenesis of autism and may eventually lead to potential treatment for autism and other neurodevelopmental disorders. Our research topic entitled Neural and Synaptic Defects in Autism Spectrum Disorders, brings together 23 articles which document the recent development and ideas in the study of molecular/cellular mechanisms and treatment of ASDs, with an emphasis on syndromic disorders such as fragile X and Rett syndromes. In addition, model systems and methodological approaches with translational relevance to autism are covered in this research topic.
    Frontiers in Cellular Neuroscience 05/2015; 9:183. DOI:10.3389/fncel.2015.00183 · 4.29 Impact Factor
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    • "revious work , we have shown that 5 - HT , through activation of 5 - HT 7 receptors , is able to reverse exaggerated mGluR - LTD in the Fmr1 KO mouse model of Fragile X Syndrome ( FXS ) ( Costa et al . , 2012a ) . Exaggerated mGluR - LTD in Fmr1 KO mice is considered an electrophysiological readout of abnormal signal - ing through mGlu receptors ( Bhakar et al . , 2012 ) . Our current hypothesis is that activation of 5 - HT 7 receptors , by correct - ing mGluR - mediated mechanisms in Fmr1 KO mice , besides reversing abnormal mGluR - LTD can also rescue other typical phenotypes of FXS , particularly abnormal dendrite morphol - ogy , cognitive impairment and autistic behavior ( Osterweil et al . , 2012"
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    ABSTRACT: Serotonin 5-HT7 receptors are expressed in the hippocampus and modulate the excitability of hippocampal neurons. We have previously shown that 5-HT7 receptors modulate glutamate-mediated hippocampal synaptic transmission and long-term synaptic plasticity. In particular, we have shown that activation of 5-HT7 receptors reversed metabotropic glutamate receptor-mediated long-term depression (mGluR-LTD) in wild-type (wt) and in Fmr1 KO mice, a mouse model of Fragile X Syndrome in which mGluR-LTD is abnormally enhanced, suggesting that 5-HT7 receptor agonists might be envisaged as a novel therapeutic strategy for Fragile X Syndrome. In this perspective, we have characterized the basic in vitro pharmacokinetic properties of novel molecules with high binding affinity and selectivity for 5-HT7 receptors and we have tested their effects on synaptic plasticity using patch clamp on acute hippocampal slices. Here we show that LP-211, a high affinity selective agonist of 5-HT7 receptors, reverses mGluR-LTD in wt and Fmr1 KO mice, correcting a synaptic malfunction in the mouse model of Fragile X Syndrome. Among novel putative agonists of 5-HT7 receptors, the compound BA-10 displayed improved affinity and selectivity for 5-HT7 receptors and improved in vitro pharmacokinetic properties with respect to LP-211. BA-10 significantly reversed mGluR-LTD in the CA3-CA1 synapse in wt and Fmr1KO mice, indicating that BA-10 behaved as a highly effective agonist of 5-HT7 receptors and reduced exaggerated mGluR-LTD in a mouse model of Fragile X Syndrome. On the other side, the compounds RA-7 and PM-20, respectively arising from in vivo metabolism of LP-211 and BA-10, had no effect on mGluR-LTD thus did not behave as agonists of 5-HT7 receptors in our conditions. The present results provide information about the structure-activity relationship of novel 5-HT7 receptor agonists and indicate that LP-211 and BA-10 might be used as novel pharmacological tools for the therapy of Fragile X Syndrome.
    Frontiers in Behavioral Neuroscience 03/2015; 9:65. doi: 10.3389/fnbeh.2015.00065. DOI:10.3389/fnbeh.2015.00065 · 3.27 Impact Factor
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