Fragile X
Fragile X
Emily Osterweil
The Osterweil lab is recruiting a motivated individual to fill a Wellcome Trust funded postdoctoral position in the Centre for Discovery Brain Sciences at the University of Edinburgh. We are studying mRNA translation in specific neural circuits, and investigating how disruptions lead to autism and intellectual disability. Our work uses cutting-edge molecular techniques, including cell type-specific TRAP-seq, ribosome profiling and single-cell RNA-seq, and combines them with electrophysiology and behavior to assess how circuit-specific changes in translation alter learning in autism models. This approach continues to identify novel therapeutic strategies. The post requires relevant experience in Neuroscience research, with a PhD either obtained or expected within 6 months of the start of the contract. The applicant must have experience with molecular biology and a working knowledge of RNA-seq analysis and/or related bioinformatics processing. This is a full-time post. Interested applicants should send a CV and letters of reference to Emily.osterweil@ed.ac.uk. Lab website: https://www.osterlab.org/
Emily Osterweil
The Osterweil lab is recruiting a motivated individual to fill a Wellcome Trust funded postdoctoral position in the Centre for Discovery Brain Sciences at the University of Edinburgh. We are studying mRNA translation in specific neural circuits, and investigating how disruptions lead to autism and intellectual disability. Our work uses cutting-edge molecular techniques, including cell type-specific TRAP-seq, ribosome profiling and single-cell RNA-seq, and combines them with electrophysiology and behavior to assess how circuit-specific changes in translation alter learning in autism models. This approach continues to identify novel therapeutic strategies.
Dr Emily Osterweil
The Osterweil lab is recruiting a motivated individual to fill a postdoctoral position in cellular neuroscience and bioinformatics. You will be joining the exceptional group of scientists in the Centre for Discovery Brain Sciences and the Simons Centre for the Developing Brain at the University of Edinburgh, recently ranked as the 16th best university in the world. You will be working in Edinburgh, one of the world’s most liveable cities with access to world-class cultural activities, UNESCO Heritage sites and unparalleled outdoor experiences. The laboratory’s research sits at the interface of cellular neuroscience and disease, seeking to address the role of mRNA translation in autism-related neurodevelopmental disorders. You will use cutting edge approaches such as TRAP-seq, Ribo-seq and scRNA-seq to discover how alterations in specific neural circuits contribute to disruptions in circuit function and behavior in animal models of autism. This Wellcome Trust funded position will use these approaches to answer critical questions about how ribosome expression changes mRNA translation in hippocampal and cortical circuits, and how this process may be targeted for therapeutic intervention in mouse models of autism. The post requires relevant experience in bioinformatics analysis of RNA-seq datasets, and experience with scRNA-seq datasets is desired. Candidates must have a PhD in cell biology, neuroscience or a related topic either obtained or expected within 6 months of the start of the contract. This is a full-time post, and start date is flexible. Applications will be reviewed on a rolling basis with a soft deadline of Aug 21. Interested applicants should send a CV and letters of reference to Emily.osterweil@ed.ac.uk. Lab website: https://www.osterlab.org/ University of Edinburgh: https://www.ed.ac.uk/ Simons Centre for the Developing Brain: https://www.sidb.org.uk/ Centre for Discovery Brain Sciences: https://www.ed.ac.uk/discovery-brain-sciences Further Reading 1) Thomson SR*, Seo SS*, Barnes SA✝, Louros SR✝, Muscas M, Dando O, Kirby C, Hardingham GE, Wyllie DJA, Kind PC, and Osterweil EK. Cell type-specific translation profiling reveals a novel strategy for treating fragile X syndrome. Neuron. 2017 Aug 2; 95(3):550-563.e5. doi: 10.1016/j.neuron.2017.07.013. 2) Stoppel LJ, Osterweil EK, and Bear MF. The mGluR Theory of fragile X syndrome. Fragile X Syndrome: From Genetics to Targeted Treatment. Willemsen, R. & Kooy, F. (Eds.). Academic Press, 2017. ISBN: 0128045078, 9780128045077. 3) Asiminas A*, Jackson AD*, Louros S†, Till SM†, Spano T, Dando O, Bear MF, Chattarji S, Hardingham GE, Osterweil EK, Wyllie DJA, Wood ER, and Kind PC. Sustained correction of associative learning deficits following brief, early treatment in a rat model of Fragile X Syndrome. Science Translational Medicine. 2019 May 29;11(494). pii: eaao0498. doi: 10.1126/scitranslmed.aao0498.
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
On the role of the ADNP gene in mice and man
(Dys)regulation of the social brain
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.
AutSim: Principled, data driven model development and abstraction for signaling in synaptic protein synthesis in Fragile X Syndrome (FXS) and healthy control.
COSYNE 2022
Cellular response to oxidative stress and senescence in Fmr1 knockout mice modelling Fragile X Syndrome
FENS Forum 2024
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
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
Exploring the molecular and morpho-functional differences in a knock-in model of Fragile X syndrome
FENS Forum 2024
Hippocampal replay events are impaired in a rat model of Fragile X Syndrome
FENS Forum 2024
Impaired hippocampal CA2 place cell responses to social odors in a rat model of Fragile X Syndrome
FENS Forum 2024
The NKCC1 inhibitor bumetanide restores cortical feedforward inhibition and lessens sensory hypersensitivity in early postnatal Fragile X mice
FENS Forum 2024
Representation of high and low frequency mouse vocalizations in the auditory midbrain and amygdala of Fragile X mice
FENS Forum 2024
Whole-brain perineuronal net and parvalbumin expression analysis in Fragile X syndrome mice
FENS Forum 2024