Toward Fulfilling the Promise of Molecular Medicine in Fragile X

The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Annual review of medicine (Impact Factor: 12.93). 02/2011; 62(1):411-29. DOI: 10.1146/annurev-med-061109-134644
Source: PubMed


Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.

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    • "Abbreviations: CAK b, cell adhesion kinase-b; CREB, cyclic AMP response binding protein; DAG, diacylglycerol; ER, endoplasmic reticulum; GKAP, guanylate kinase associated protein; Gq/Gq11, guanine nucleotide binding protein q/q11; IP3, inositol 1,4,5 trisphosphate; NMDA, N-methyl-D-aspartate; GRM5/mGluR5, metabotropic glutamate receptor-5; MAPK, mitogen activated protein kinase; PIP2, Phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLCB1, phospholipase C-beta 1; PSD95, post-synaptic density 95; SHANK3, SH3 and multiple ankyrin repeat domain. symptomatology (Krueger and Bear, 2011). Recently, we have found that single nucleotide polymorphisms (SNPs) in GRM5 (the gene encoding mGluR5) had a strong weighting in our predictive genetic classifier for ASD (Skafidas et al., 2014). "
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    ABSTRACT: Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, while activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p = 0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p = 0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 06/2015; 49. DOI:10.1016/j.bbi.2015.05.009 · 5.89 Impact Factor
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    • "Fragile X and Rett syndromes are leading the way in investigating the molecular mechanisms of autism (Krueger and Bear, 2011; Katz et al., 2012; Santoro et al., 2012). Fragile X mental retardation protein (FMRP) is an mRNA binding protein absent or mutated in fragile X syndrome (Bhakar et al., 2012; Santoro et al., 2012; Wang, 2015). "
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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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    • "The lack of FMRP causes the fragile X syndrome (FXS) which is the most common cause of inherited mental retardation and autism spectrum disorders (ASD; Krueger and Bear, 2011). In response to the metabotropic glutamate receptor (mGluR) activation , FMRP mediates the activity-dependent dendritic mRNA transport and translation (Bagni and Greenough, 2005; Kao et al., 2010; Tatavarty et al., 2012). "
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    ABSTRACT: Thyroid hormones are fundamental for the expression of genes involved in the development of the CNS and their deficiency is associated with a wide spectrum of neurological diseases including mental retardation, attention deficit-hyperactivity disorder and autism spectrum disorders. We examined in rat whether developmental and early postnatal hypothyroidism affects the distribution of vesicular glutamate transporter-1 (VGluT1; glutamatergic) and vesicular inhibitory amino acid transporter (VGAT; GABAergic) immunoreactive (ir) boutons in the hippocampus and somatosensory cortex, and the behavior of the pups. Hypothyroidism was induced by adding 0.02% methimazole (MMI) and 1% KClO 4 to the drinking water starting at embryonic day 10 (E10; developmental hypothyroidism) and E21 (early postnatal hypothyroidism) until day of sacrifice at postnatal day 50. Behavior was studied using the acoustic prepulse inhibition (somatosensory attention) and the elevated plus-maze (anxiety-like assessment) tests. The distribution, density and size of VGluT1-ir and VGAT-ir boutons in the hippocampus and somatosensory cortex was abnormal in MMI pups and these changes correlate with behavioral changes, as prepulse inhibition of the startle response amplitude was reduced, and the percentage of time spent in open arms increased. In conclusion, both developmental and early postnatal hypothyroidism significantly decreases the ratio of GABAergic to glutamatergic boutons in dentate gyrus leading to an abnormal flow of information to the hippocampus and infragranular layers of the somatosensory cortex, and alter behavior in rats. Our data show cytoarchitectonic alterations in the basic excitatory hippocampal loop, and in local inhibitory circuits of the somatosensory cortex and hippocampus that might contribute to the delayed neurocognitive outcome observed in thyroid hormone deficient children born in iodine deficient areas, or suffering from congenital hypothyroidism.
    Frontiers in Neuroanatomy 03/2015; 9. DOI:10.3389/fnana.2015.00009 · 3.54 Impact Factor
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