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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Available from: Mark F Bear, Nov 13, 2014
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    • "This discovery led to the mGluR theory of FXS[1], which suggests that many of its clinical features are due to exaggerated responses to activation of mGluR5. This theory was validated when multiple FXS phenotypes were rescued in Fmr1KO mice by reducing the production of mGluR5 protein567. Neurons from Fmr1KO mice and from patients with FXS consistently have increased spine densities, as well as longer spines, reminiscent of immature filopodia[5,891011. "
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    ABSTRACT: Fragile X syndrome (FXS) is a neurodevelopmental disorder whose biochemical manifestations involve dysregulation of mGluR5-dependent pathways, which are widely modeled using cultured neurons. In vitro phenotypes in cultured neurons using standard morphological, functional, and chemical approaches have demonstrated considerable variability. Here, we study transcriptomes obtained in situ in the intact brain tissues of a murine model of FXS to see how they reflect the in vitro state. Methods We used genome-wide mRNA expression profiling as a robust characterization tool for studying differentially expressed pathways in fragile X mental retardation 1 (Fmr1) knockout (KO) and wild-type (WT) murine primary neuronal cultures and in embryonic hippocampal and cortical murine tissue. To study the developmental trajectory and to relate mouse model data to human data, we used an expression map of human development to plot murine differentially expressed genes in KO/WT cultures and brain. Results We found that transcriptomes from cell cultures showed a stronger signature of Fmr1KO than whole tissue transcriptomes. We observed an over-representation of immunological signaling pathways in embryonic Fmr1KO cortical and hippocampal tissues and over-represented mGluR5-downstream signaling pathways in Fmr1KO cortical and hippocampal primary cultures. Genes whose expression was up-regulated in Fmr1KO murine cultures tended to peak early in human development, whereas differentially expressed genes in embryonic cortical and hippocampal tissues clustered with genes expressed later in human development. Conclusions The transcriptional profile in brain tissues primarily centered on immunological mechanisms, whereas the profiles from cell cultures showed defects in neuronal activity. We speculate that the isolation and culturing of neurons caused a shift in neurological transcriptome towards a “juvenile” or “de-differentiated” state. Moreover, cultured neurons lack the close coupling with glia that might be responsible for the immunological phenotype in the intact brain. Our results suggest that cultured cells may recapitulate an early phase of the disease, which is also less obscured with a consequent “immunological” phenotype and in vivo compensatory mechanisms observed in the embryonic brain. Together, these results suggest that the transcriptome of cultured primary neuronal cells, in comparison to whole brain tissue, more robustly demonstrated the difference between Fmr1KO and WT mice and might reveal a molecular phenotype, which is typically hidden by compensatory mechanisms present in vivo. Moreover, cultures might be useful for investigating the perturbed pathways in early human brain development and genes previously implicated in autism.
    Full-text · Article · Dec 2015 · Molecular 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.
    Full-text · Article · Jun 2015 · Brain Behavior and Immunity
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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.
    Full-text · Article · May 2015 · Frontiers in Cellular Neuroscience
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