Article

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

ABSTRACT

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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    • "These medications include psychoactive drugs or anticonvulsants, with the most common drug classes being antidepressants, stimulants, and antipsychotics[16]but such medications may have adverse effects[11]and no known medication relieves autism's core symptoms of social and communication impairments[17]. Animal studies have reversed or reduced some symptoms related to autism by replacing or modulating gene function[18],[19]suggesting the possibility of targeting therapies to specific rare mutations known to cause autism[20],[21]. Although many alternative therapies and interventions are available; few are supported by scientific studies. "

    Full-text · Article · Jan 2016
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    • "These phenotypes can be recapitulated in cultured neurons[12,13]. They can be corrected by treatment with mGluR5 antagonists in both cultured neurons and mice[5,13]. Thus, in vitro models derived from Fmr1KO mice are reasonable platforms for modeling synaptic alterations occurring in FXS. "
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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
    • "In contrast, Pc-ODP of the open eye responses is only seen after 5 days of MD (Fig. 1B). Previously, recordings of visually evoked potentials (VEPs) using a single implanted electrode have been used to assess ODP and study plasticity deficits in mice before and after MD (Dolen et al., 2007; Yashiro et al., 2009). "
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    ABSTRACT: BACKGROUND: Neuronal plasticity deficits are thought to underlie abnormal neurodevelopment in fetal alcohol spectrum disorders and in animal models of this condition. Previously, we found that alcohol exposure during a period that is similar to the last months of gestation in humans disrupts ocular dominance plasticity (ODP), as measured in superficial cortical layers. We hypothesize that exposure to alcohol can differentially affect the potentiation and depression of responses that are necessary for activity-dependent sprouting and pruning of neuronal networks. ODP is an established paradigm that allows the assessment of activity-dependent depression and potentiation of responses in vivo. METHODS: Mouse pups were exposed to 3.6 to 5 g/kg of ethanol in saline daily or every other day between postnatal days 4 and 9. Visual cortex plasticity was then assessed during the critical period for ODP using 2 techniques that separately record in layers 4 (visually evoked potentials [VEPs]) and 2/3 (optical imaging of intrinsic signals [OI]). RESULTS: We discovered a layer-specific effect of early alcohol exposure. Recording of VEPs from layer 4 showed that while the potentiation component of ODP was disrupted in animals treated with alcohol when compared with saline controls, the depression component of ODP (Dc-ODP) was unaltered. In contrast, OI from layers 2/3 showed that Dc-ODP was markedly disrupted in alcohol-treated animals when compared with controls. CONCLUSIONS: Combined with our previous work, these findings strongly suggest that developmental alcohol exposure has a distinct and layer-specific effect on the potentiation and depression of cortical responses after monocular deprivation.
    No preview · Article · Jun 2015 · Alcoholism Clinical and Experimental Research
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