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Identifying mistranslating mRNAs in specific neural circuits of mouse models of autism


About This PhD Project

Project Description

Project Code: 2020-SIDB-05

Aberrant neuronal protein synthesis is a point of convergence for multiple genetic causes of autism. Notably, excessive synaptic protein synthesis has been identified as a core cellular phenotype in the Fmr1-/y mouse model Fragile X Syndrome (FX), the most commonly identified single-gene cause of autism. Treatments that normalize protein synthesis in the Fmr1-/y model correct multiple electrophysiological and behavioural phenotypes, and this has led to the development of therapeutic strategies currently in clinical trials. However, the mechanism underlying excessive neuronal protein synthesis in FX is not known. Furthermore, we have not identified the mistranslating mRNAs that cause specific impairments in neural function. This information is critical not only for understanding the pathogenesis of autism but for designing rational treatment strategies.

The goal of this PhD project is to identify mistranslating mRNAs that contribute to altered behavior in Fmr1-/y and Syngap+/- mouse models.

In order to identify mistranslating mRNAs in specific neuron populations we are using Translating Ribosome Affinity Purification and RNA sequencing (TRAP-seq). In this project, TRAP-seq will be used to identify mistranslating mRNAs in specific neurons of the Fmr1-/y and Syngap+/- mouse models of autism, both of which exhibit excessive cerebral protein synthesis[5]. The focus will be on brain regions involved in altered learning and behaviour in these models, including hippocampus, amygdala and prefrontal cortex. TRAP-seq will be performed during learning to determine how behaviour shapes the translating mRNA populations in these neurons. In addition, single-cell RNA-seq (scRNA-seq) will be employed to identify transcriptomic changes in specific neuron populations during development. Ultimately, targets identified in these experiments will be tested as candidates for therapeutic intervention using multiple behavioural and electrophysiological assays as in previous studies.

Technical approaches involved in the project include:

1. TRAP isolation of translating mRNAs in specific neuronal cell populations
2. RNA sequencing and bioinformatics analysis
3. scRNA-seq and associated informatics analysis
4. Techniques in molecular biology (i.e., qPCR) and protein biochemistry (i.e., immunoblotting)
5. Immunohistochemistry and confocal imaging
6. Behavioral analyses of mouse models

References

1. Kelleher, R.J., 3rd and M.F. Bear, The autistic neuron: troubled translation? Cell, 2008. 135(3): p. 401-6.

2. Auerbach, B.D., E.K. Osterweil, and M.F. Bear, Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature, 2011.480(7375): p. 63-8.

3. Stoppel, L.J., E.K. Osterweil, and M.F. Bear, The mGluR Theory From Mice to Men, in Fragile X Syndrome: From Genetics to Targeted Treatment R. Willemsen and F. Kooy, Editors. 2017, Elsevier.

4. Thomson, S.R., et al., Cell-Type-Specific Translation Profiling Reveals a Novel Strategy for Treating Fragile X Syndrome. Neuron, 2017. 95(3): p. 550-563 e5.

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