Fragile X syndrome and autism at the intersection of genetic and neural networks

Belmonte, Matthew K.; Bourgeron, Thomas

doi:10.1038/nn1765

Cited by 283 publications

(238 citation statements)

References 49 publications

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“…A possible example of this is provided by a previous report suggesting that autistic patients who have disrupted FMR1 function disproportionately involve mosaic FMRP expression (Reddy, 2005). That both altered functional connectivity and autistic phenotypes could result from mosaic FMR1 expression is intriguing given that abnormal functional connectivity and disrupted information carrying capacity of neural networks play central roles in theories about the neural substrates of autism (Belmonte and Bourgeron, 2006). This underscores the importance of testing for links between mosaic FMRP expression and autistic phenotypes in future studies of large cohorts of ASD and FXS patients.…”

Section: Discussionmentioning

confidence: 99%

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson¹,

Madison²

2007

J. Neurosci.

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Almost all female and some male fragile X syndrome (FXS) patients are mosaic for expression of the FMR1 gene, yet all research in models of FXS has been in animals uniformly lacking Fmr1 expression. Therefore, we developed a system allowing neuronal genotype to be visualized in vitro in mouse brain slices mosaic for Fmr1 expression. Whole-cell recordings from individual pairs of presynaptic and postsynaptic neurons in organotypic hippocampal slices were used to probe the cell-autonomous effects of Fmr1 genotype in mosaic networks. These recordings revealed that wild-type presynaptic neurons formed synaptic connections at a greater rate than presynaptic neurons lacking normal Fmr1 function in mosaic networks. At the same time, the postsynaptic Fmr1 genotype did not influence the probability that a neuron received synaptic connections. Asymmetric presynaptic function during development of the brain could result in a decreased participation in network function by the portion of neurons lacking FMR1 expression.

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Section: Discussionmentioning

confidence: 99%

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Hanson¹,

Madison²

2007

J. Neurosci.

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“…In contrast to the wide heterogeneity of autism-associated genes, FXS is caused by the silencing of FMR-1 that codes for FMRP 73 . Although most cases of autism are not associated with FXS, the prevalence of autism in FXS is estimated to range from 5% to 60% 74 . FXS is the most common form of inherited intellectual disability, with the patients displaying dendritic spine defects 75 ,…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…FXS is a frequent monogenic cause of ASD 74,[76][77][78] and the behavioral overlap between autism and FXS patients suggests overlapping neuronal network mechanisms that increase susceptibility to ASD. The regulatory function of CYFIP1 in the context of FMRP-and WAVE-containing complexes and subsequent actin remodeling may explain the convergence of these two neurodevelopmental disorders.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Dendritic spine actin cytoskeleton in autism spectrum disorder

Joensuu¹,

Lanoue

Hotulainen

2018

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…135). In some idiopathic cases, the disease phenotype might be driven by mild epigenetic abnormalities involving imprinted regions of 15q11-13, in combination with one or more loci conferring susceptibility to core symptoms.…”

Section: Autism Candidate Genes and Synaptic Functionmentioning

confidence: 99%

Advances in behavioral genetics: mouse models of autism

2007

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Autism is a neurodevelopmental syndrome with markedly high heritability. The diagnostic indicators of autism are core behavioral symptoms, rather than definitive neuropathological markers. Etiology is thought to involve complex, multigenic interactions and possible environmental contributions. In this review, we focus on genetic pathways with multiple members represented in autism candidate gene lists. Many of these pathways can also be impinged upon by environmental risk factors associated with the disorder. The mouse model system provides a method to experimentally manipulate candidate genes for autism susceptibility, and to use environmental challenges to drive aberrant gene expression and cell pathology early in development. Mouse models for fragile X syndrome, Rett syndrome and other disorders associated with autistic-like behavior have elucidated neuropathology that might underlie the autism phenotype, including abnormalities in synaptic plasticity. Mouse models have also been used to investigate the effects of alterations in signaling pathways on neuronal migration, neurotransmission and brain anatomy, relevant to findings in autistic populations. Advances have included the evaluation of mouse models with behavioral assays designed to reflect disease symptoms, including impaired social interaction, communication deficits and repetitive behaviors, and the symptom onset during the neonatal period. Research focusing on the effect of gene-by-gene interactions or genetic susceptibility to detrimental environmental challenges may further understanding of the complex etiology for autism.

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Fragile X syndrome and autism at the intersection of genetic and neural networks

Cited by 283 publications

References 49 publications

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

PresynapticFmr1Genotype Influences the Degree of Synaptic Connectivity in a Mosaic Mouse Model of Fragile X Syndrome

Dendritic spine actin cytoskeleton in autism spectrum disorder

Advances in behavioral genetics: mouse models of autism

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