Fragile X syndrome
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Freeze or flee ? New insights from rodent models of autism
Individuals afflicted with certain types of autism spectrum disorder often exhibit impaired cognitive function alongside enhanced emotional symptoms and mood lability. However, current understanding of the pathogenesis of autism and intellectual disabilities is based primarily on studies in the hippocampus and cortex, brain areas involved in cognitive function. But, these disorders are also associated with strong emotional symptoms, which are likely to involve changes in the amygdala and other brain areas. In this talk I will highlight these issues by presenting analyses in rat models of ASD/ID lacking Nlgn3 and Frm1 (causing Fragile X Syndrome). In addition to identifying new circuit and cellular alterations underlying divergent patterns of fear expression, these findings also suggest novel therapeutic strategies.
From symptoms to circuits in Fragile X syndrome
Dysregulated Translation in Fragile X Syndrome
Neural impairments in Fragile X Syndrome
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.
Sensory representation variability during neurodevelopment in Fragile X Syndrome
Control of neural precursor cells proliferation and differentiation by the Fragile X messenger ribonucleoprotein 1 (FMRP): Insights into the etiology of Fragile X Syndrome
FENS Forum 2024
Exploring the molecular and morpho-functional differences in a knock-in model of Fragile X syndrome
FENS Forum 2024
AutSim: Principled, data driven model development and abstraction for signaling in synaptic protein synthesis in Fragile X Syndrome (FXS) and healthy control.
COSYNE 2022
Autistic-like behavioral effects of prenatal stress in the Fmr1-KO mouse model of Fragile X syndrome
Cognitive deficits in mouse model of Fragile X Syndrome reflect specific memory ensemble recruitment failure along the ventral hippocampus-prelimbic cortex axis
Coordination of BET family proteins in Fragile X Syndrome
Facilitating mGlu4 receptor activity relieves autistic-like behaviors in a mouse model of Fragile X Syndrome
High-throughput analysis in a fragile X syndrome mouse model after CB1 receptor targeting reveals specific transcriptomic signature sensitive to treatment
Hypersynchronised gamma oscillations in the medial prefrontal cortex and hippocampus in a rat model of Fragile X Syndrome
Impaired Pattern Completion during Memory Recall in a Mouse Model of Fragile X Syndrome
Impaired hippocampal CA2 place cell responses to social odors in a rat model of Fragile X Syndrome
FENS Forum 2024
iPSC-derived cortical neurons and patterned cortical organoids to dissect the neurodevelopmental roots of Fragile X Syndrome
Migration defects in Fragile X Syndrome
Neuroplasticity profile and neurogenic activity in Fmr1 Knock out rats, a Model of the fragile X Syndrome
Cellular response to oxidative stress and senescence in Fmr1 knockout mice modelling Fragile X Syndrome
FENS Forum 2024
Distinct trajectories of oligodendrocyte development in the genetic mosaic brain of female mouse model of Fragile X syndrome
FENS Forum 2024
ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome
FENS Forum 2024
Hippocampal replay events are impaired in a rat model of Fragile X Syndrome
FENS Forum 2024
Whole-brain perineuronal net and parvalbumin expression analysis in Fragile X syndrome mice
FENS Forum 2024
Fragile X syndrome coverage
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