FMR1

Molecular Biology of the Fragile X Syndrome

Silencing of FMR1 and loss of its gene product, FMRP, results in fragile X syndrome (FXS). FMRP binds brain mRNAs and inhibits polypeptide elongation. Using ribosome profiling of the hippocampus, we find that ribosome footprint levels in Fmr1-deficient tissue mostly reflect changes in RNA abundance. Profiling over a time course of ribosome runoff in wild-type tissue reveals a wide range of ribosome translocation rates; on many mRNAs, the ribosomes are stalled. Sucrose gradient ultracentrifugation of hippocampal slices after ribosome runoff reveals that FMRP co-sediments with stalled ribosomes, and its loss results in decline of ribosome stalling on specific mRNAs. One such mRNA encodes SETD2, a lysine methyltransferase that catalyzes H3K36me3. Chromatin immunoprecipitation sequencing (ChIP-seq) demonstrates that loss of FMRP alters the deployment of this histone mark. H3K36me3 is associated with alternative pre-RNA processing, which we find occurs in an FMRP-dependent manner on transcripts linked to neural function and autism spectrum disorders.

Circuit dysfunction and sensory processing in Fragile X Syndrome

To uncover the circuit-level alterations that underlie atypical sensory processing associated with autism, we have adopted a symptom-to-circuit approach in theFmr1-/- mouse model of Fragile X syndrome (FXS). Using a go/no-go task and in vivo 2-photon calcium imaging, we find that impaired visual discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons in primary visual cortex, and a decrease in the activity of parvalbumin (PV) interneurons. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioural performance. Strikingly, human subjects with FXS exhibit similar impairments in visual discrimination as Fmr1-/- mice. These results suggest that manipulating inhibition may help sensory processing in FXS. More recently, we find that the ability of Fmr1-/- mice to perform the visual discrimination task is also drastically impaired in the presence of visual or auditory distractors, suggesting that sensory hypersensitivity may affect perceptual learning in autism.

Fmr1-KO mouse model, a suitable tool to study Autism Spectrum Disorder (ASD)

Autistic-like behavioral effects of prenatal stress in the Fmr1-KO mouse model of Fragile X syndrome

Cannabidiol rescues autistic-like symptoms in a genetic model of autism based on FMR1 deletion in rats

Ciliopathy in Meningeal Fibroblast Accompanying the Delayed Maturation of Pial Basement Membrane during Cortical Development of Fmr1-/y Mice

Comparative analysis of exosome proteomic profiling between neurons and astrocytes of Fmr1 knockout mouse

FMR1 KO mice exhibit deficits in behavior, eye alignment, and cortical activity during stereoscopic depth discrimination compared to wild type mice

Lack of Fmr1-gene impacts early development of vocal communication particularly in female mouse pups

Neuroplasticity profile and neurogenic activity in Fmr1 Knock out rats, a Model of the fragile X Syndrome

Role of the endocannabinoid system in a genetic model of autism based on FMR1 deletion in rats

Cellular response to oxidative stress and senescence in Fmr1 knockout mice modelling Fragile X Syndrome

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The effect of imprinted inheritance on embryonic mouse brain development in the Fmr1-KO parent-derived offspring

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Maternal Fmr1 deficiency dysregulates offspring sociability and oxytocinergic signaling in the VTA

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Prefrontal cortex alterations underlying attentional modulation of sensory information in the Fmr1KO mouse model of autism spectrum disorder

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