Correction of Fragile X Syndrome in Mice

Howard Hughes Medical Institute, The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Neuron (Impact Factor: 15.05). 01/2008; 56(6):955-62. DOI: 10.1016/j.neuron.2007.12.001
Source: PubMed


Fragile X syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 expression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for fragile X and related developmental disorders.

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Available from: Sumantra Chattarji, Jan 23, 2014
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    • "Fmr1-ko mice were then shown to display abnormal long-term depression due to excessive mGluR5 signaling and internalization of AMPA glutamate receptors: the " mGluR theory " of FraX thus lays the foundation of FraX pathophysiology upon three consequences of the absence of FMRP, namely: (a) excessive mGluR1/5 stimulation, (b) enhanced local protein synthesis, and (c) undue internalization of AMPA receptors (Bear et al., 2004). Indeed, a remarkable reversal of excessive protein synthesis, dendritic spine alterations and abnormal behavioural phenotypes was observed in Fmr1-ko mice by blunting mGluR5 signaling through genetic strategies (Dölen et al., 2007) or by administering the mGluR1/5 antagonist MPEP (Yan et al., 2005; de Vrij et al., 2008). Despite this wealth of preclinical evidence strongly supporting the promising efficacy of mGluR5 antagonists in FraX and possibly in ASD, one preliminary clinical study of an mGluR5 antagonist failed to reach its endpoints in adult FraX subjects, though showing some promise in the subgroup of patients carrying complete methylation of the FMR1 promoter (Jacquemont et al., 2011). "
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    ABSTRACT: Paediatric psychopharmacology holds great promise in two equally important areas of enormous biomedical and social impact, namely the treatment of behavioural abnormalities in children and adolescents, and the prevention of psychiatric disorders with adolescent- or adult-onset. Yet, in striking contrast, pharmacological treatment options presently available in child and adolescent psychiatry are dramatically limited. The most important currently unmet needs in paediatric psychopharmacology are: the frequent off-label prescription of medications to children and adolescents based exclusively on data from randomized controlled studies involving adult patients; the frequent lack of age-specific dose, long-term efficacy and tolerability/safety data; the lack of effective medications for many paediatric psychiatric disorders, most critically autism spectrum disorder; the scarcity and limitations of randomized placebo-controlled trials in paediatric psychopharmacology; the unexplored potential for the prevention of psychiatric disorders with adolescent- and adult-onset; the current lack of biomarkers to predict treatment response and severe adverse effects; the need for better preclinical data to foster the successful development of novel drug therapies; and the effective dissemination of evidence-based treatments to the general public, to better inform patients and families of the benefits and risks of pharmacological interventions during development. Priorities and strategies are proposed to overcome some of these limitations, including the European Child and Adolescent Clinical Psychopharmacology Network, as an overarching Pan-European infrastructure aimed at reliably carrying out much needed psychopharmacological trials in children and adolescents, in order to fill the identified gaps and improve overall outcomes. Copyright © 2015 Elsevier B.V. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 06/2015; DOI:10.1016/j.euroneuro.2015.06.009 · 4.37 Impact Factor
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    • "Numerous studies have reported exaggerated signaling of mGlu1/5 receptors in FXS animal models (Dö len et al., 2007; Huber et al., 2002; Muddashetty et al., 2007; Osterweil et al., 2010; Ronesi et al., 2012), and mGlu5 negative allosteric modulators have been shown to rescue many FXS-associated phenotypes (McBride et al., 2005; Michalon et al., 2012; Yan et al., 2005). Several recent studies have begun to analyze the molecular mechanisms of dysregulated mGlu1/5 signaling in FXS by genetically reducing or deleting mGlu1/5-signaling complex components or downstream regulators of protein synthesis (Bhattacharya et al., 2012; Dö len et al., 2007; Ronesi et al., 2012), but the detailed underlying molecular mechanisms are still unknown . In this study, we show that the PI3K enzymatic activity of the mGlu5 protein complex is increased in Fmr1 KO cortex Figure 3. Genetic Reduction of Centg1 Reduces Neocortical Hyperactivity and Repetitive Behaviors and Improves Nest Building in Fmr1 KO Mice (A and B) Genetic reduction of Centg1 decreases duration of UP states in acute thalamocortical slices from Fmr1 KO mice. "
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    ABSTRACT: The PI3K enhancer PIKE links PI3K catalytic subunits to group 1 metabotropic glutamate receptors (mGlu1/5) and activates PI3K signaling. The roles of PIKE in synaptic plasticity and the etiology of mental disorders are unknown. Here, we show that increased PIKE expression is a key mediator of impaired mGlu1/5-dependent neuronal plasticity in mouse and fly models of the inherited intellectual disability fragile X syndrome (FXS). Normalizing elevated PIKE protein levels in FXS mice reversed deficits in molecular and cellular plasticity and improved behavior. Notably, PIKE reduction rescued PI3K-dependent and -independent neuronal defects in FXS. We further show that PI3K signaling is increased in a fly model of FXS and that genetic reduction of the Drosophila ortholog of PIKE, CenG1A rescued excessive PI3K signaling, mushroom body defects, and impaired short-term memory in these flies. Our results demonstrate a crucial role of increased PIKE expression in exaggerated mGlu1/5 signaling causing neuronal defects in FXS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(5). DOI:10.1016/j.celrep.2015.03.060 · 8.36 Impact Factor
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    • "The brain of FXS patients shows abnormal dendrite morphology in cortex and hippocampus, with an overproduction of long, thin and immature dendritic spines (Irwin et al., 2000). Evidence of synapse malfunction came from studies on the Fmr1 gene knockout (Fmr1 KO) mouse, an animal model of FXS that displays typical features resembling those of FXS patients, among which alterations in dendritic spine morphology (Comery et al., 1997; Nimchinsky et al., 2001) increased susceptibility to audiogenic seizures (Musumeci et al., 2000) and cognitive impairment (Bernardet and Crusio, 2006; Dolen et al., 2007). In vitro studies on Fmr1 KO mice revealed that the lack of FMRP dysregulates protein translation induced by activation of group I metabotropic glutamate receptors (mGluRs), with an overproduction of proteins involved in AMPA receptor endocytosis (Nakamoto et al., 2007). "
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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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