Development of White Matter Circuitry in Infants With Fragile X Syndrome

Swanson, Meghan R.; Wolff, Jason J.; Shen, Mark D.; Styner, Martin; Estes, Annette; Gerig, Guido; McKinstry, Robert C.; Botteron, Kelly N.; Piven, Joseph; Hazlett, Heather C.

doi:10.1001/jamapsychiatry.2018.0180

Cited by 39 publications

(43 citation statements)

References 60 publications

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“…In addition, in vivo imaging of FXS mice shows an anatomical hyperconnectivity phenotype in the primary visual cortex but a disproportional low connectivity with other neocortical regions (Haberl et al, 2015;Zerbi et al, 2018). These observations are consistent with findings in FXS human infants at the onset of the critical period, who exhibit an increased density of DTI-reconstructed fibers relative to that of normal children (Haas et al, 2009;Swanson et al, 2018).…”

Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CIsupporting

confidence: 86%

“…Likewise, suboptimal levels of FMRP in the developing brain appear to be detrimental for brain wiring (Dennis and Thompson, 2013). Imaging studies in humans with FXS (Swanson et al, 2018) and ASDs (Ha et al, 2015) reveal aberrant structure of multiple brain regions. Specifically, long-range FC is altered in ASD and FXS patients (Hall et al, 2013;Holsen et al, 2008;Yerys et al, 2017).…”

Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CImentioning

confidence: 99%

“…The white matter in frontostriatal pathways, as well as in parietal sensory-motor tracts, is also affected (Barnea-Goraly et al, 2003). In addition, microstructural defects as measured by reduction in FA of white matter tracts, predominantly in the corpus callosum, have been found in both FXS individuals and mouse models (Haberl et al, 2015;Swanson et al, 2018).…”

Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CImentioning

confidence: 99%

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A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

235

258

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Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. ASDs and FXS: Causes and Clinical Features Approximately 1%-3% of the general population is affected by intellectual disabilities (IDs). IDs are neurodevelopmental disorders defined by significant limitations in intellectual functioning and adaptive behaviors and often exhibit comorbidity with autism (Mefford et al., 2012). Autism spectrum disorders (ASDs) are characterized by high phenotypic heterogeneity, comprising deficits in social interaction and communication as well as repetitive and stereotyped behaviors (

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Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CIsupporting

confidence: 86%

Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CImentioning

confidence: 99%

Section: Fxs and Asds: Common Features In Genetic Makeup And Brain CImentioning

confidence: 99%

See 1 more Smart Citation

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Bagni

Zukin

2019

Neuron

235

258

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“…Several other observed examples of dysregulated solute carriers in multiple cell types may contribute to the FXS phenotypes of mRNA translation defects and autistic behaviors through pathways other than regulation the glio and neurotransmitters as discussed above. These include genes downregulated in oligodendrocytes, such as Slc1a2 (GLT-1), involved in glutamate regulation and critical for white matter development 54,55 , or downregulated in endothelial cells, such as Slc7a5 (LAT-1), a mediator of amino acid uptake which can impact the amino acid profile and mRNA translation in the brain, causing neurological abnormalities 56 . Astrocytes in turn, show an increased expression of Slc30a10 (ZnT10), responsible for Zn 2+ and Mn 2+ transport to the extracellular space 57 .…”

Section: Figurementioning

confidence: 99%

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

Donnard

Shu

Garber

2020

Preprint

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Despite advances in understanding the pathophysiology of Fragile X syndrome (FXS), its molecular bases are still poorly understood. Whole brain tissue expression profiles have proved surprisingly uninformative. We applied single cell RNA sequencing to profile a FXS mouse model. We found that FXS results in a highly cell type specific effect and it is strongest among different neuronal types. We detected a downregulation of mRNAs bound by FMRP and this effect is prominent in neurons. Metabolic pathways including translation are significantly upregulated across all cell types with the notable exception of excitatory neurons. These effects point to a potential difference in the activity of mTOR pathways, and together with other dysregulated pathways suggest an excitatory-inhibitory imbalance in the FXS cortex which is exacerbated by astrocytes. Our data demonstrate the cell-type specific complexity of FXS and provide a resource for interrogating the biological basis of this disorder.

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“…FXS can be comorbid with epilepsy, ADHD, and anxiety [13][14][15][16], and FMRP plays prominent roles in a wide range of neural functions, including neural plasticity [17] and synaptic development [18][19][20]. Importantly, longitudinal neuroimaging has documented region-specific white matter abnormalities in individuals with FXS [21,22], thereby also implicating oligodendrocytes in the disease state.…”

Section: Introductionmentioning

confidence: 99%

The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

Doll

Yergert

Appel

2019

Preprint

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During development, oligodendrocytes in the central nervous system extend a multitude of processes that wrap axons with myelin. The highly polarized oligodendrocytes generate myelin sheaths on many different axons, which are far removed from the cell body. Neurons use RNA binding proteins to transport, stabilize, and locally translate mRNA in distal domains of neurons. Local synthesis of synaptic proteins during neurodevelopment facilitates the rapid structural and functional changes underlying neural plasticity and avoids extensive protein transport. We hypothesize that RNA binding proteins also regulate local mRNA regulation in oligodendrocytes to promote myelin sheath growth. Fragile X mental retardation protein (FMRP), an RNA binding protein that plays essential roles in the growth and maturation of neurons, is also expressed in oligodendrocytes. To determine whether oligodendrocytes require FMRP for myelin sheath development, we examined fmr1 -/mutant zebrafish and drove FMR1 expression specifically in oligodendrocytes. We found oligodendrocytes in fmr1 -/mutants developed myelin sheaths of diminished length, a phenotype that can be autonomously rescued in oligodendrocytes with FMR1 expression. Myelin basic protein (Mbp), an essential myelin protein, was reduced in myelin tracts of fmr1 -/mutants, but loss of FMRP function did not impact the localization of mbpa transcript in myelin. Finally, expression of FMR1-I304N, a missense allele that abrogates FMRP association with ribosomes, failed to rescue fmr1 -/mutant sheath growth and induced short myelin sheaths in oligodendrocytes of wild-type larvae. Taken together, these data suggest that FMRP promotes sheath growth through local regulation of translation.Entry clones were LR-recombined with either the pDEST-Tol2-CG2 destination vector (green heart marker; for pEXPR-myrf:FMR1-IRES-EGFP-CAAX and pEXPR-myrf:FMR1-I304N-IRES-EGFP-CAAX) or pDEST-Tol2-pA2 vector for pEXPR-sox10:FMR1-EGFP.Published plasmids: p3E-7.2sox10 [31],, p3E-EGFP [56]. Imaging and analysisWith the exception of smFISH and IHC, live larvae were imaged in all experiments. Larvae were embedded laterally in 1.2% low-melt agarose containing 0.4% tricaine for immobilization. We acquired images on a Zeiss CellObserver SD 25 spinning disk confocal system for time-lapse microscopy and cell counts (Carl Zeiss) or a Zeiss LSM 880 for all other experiments (Carl Zeiss). Images were captured with Zen software (Carl Zeiss), then processed and analyzed using Fiji/ImageJ or Zen Blue (Carl Zeiss).smFISH probe design mbpa smFISH probes were designed using the Stellaris RNA FISH Probe Designer tool by entering the zebrafish mbpa cDNA sequences obtained from Ensemble Genome Browser from transcript mbpa-206 (GRCz11). Probes with highly repetitive sequences were removed. The probes were ordered with a CAL Fluor® Red 610 Dye. Probes were resuspended in Tris-EDTA, pH 8.0 and stored at a stock concentration of 12.5 µM at -20°C.

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Development of White Matter Circuitry in Infants With Fragile X Syndrome

Cited by 39 publications

References 60 publications

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders

Single Cell Transcriptomics Reveals Dysregulated Cellular and Molecular Networks in a Fragile X Syndrome model

The RNA Binding Protein FMRP Promotes Myelin Sheath Growth

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