EASTBIO: Investigating the emergence of forebrain interneuron phenotypes caused by the 16p11.2 autism genetic risk factor. at University of Edinburgh on FindAPhD.com

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Dr Thomas Pratt, Dr Sam Booker No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Deanery of Biomedical Sciences:

Background: Autism is a neurodevelopmental disorder associated with numerous genetic risk factors including the polygenic 16p11.2 microdeletion. Patients heterozygous for the 16p11.2 microdeletion (16p11.2^+/-) account for about 1% of autism cases making it one of the most common genetic causes of autism. A central question is what neural cells are affected and how perturbing their development ultimately predisposes to autism. The proper functioning of the mature cerebral cortex (CC) depends on the balance between excitatory neurons (ExNs) and inhibitory interneurons (INs). The Excitatory/Inhibitory (E/I) balance is important for normal brain function and disruption to the E/I balance is hypothesised to underpin features of autism. There is accumulating evidence that the 16p11.2 microdeletion targets ExN development but this hypothesis has not been systematically tested for IN development. Consistent with the hypothesis that INs are targeted by the 16p11.2 microdeletion our bioinformatic analysis of human foetal gene expression data identifies developing INs as vulnerable to the 16p11.2 microdeletion and we observed IN hypersensitivity and elongated axon initial segments in INs from postnatal 16p11.2^+/- rats.

Hypothesis: 16p11.2 microdeletion leads to inappropriate developmental programs of IN precursors, leading to their impaired function in mature neuronal circuits.

Rationale: Understanding how the 16p11.2 microdeletion targets IN precursors as they develop is vital to understanding the 16p11.2 phenotype. An important unanswered question is how phenotypes early in the IN developmental trajectory relate to their later phenotypes and the contribution of homeostatic mechanisms compensating for early phenotypes with pathological consequences. Rodent models allow IN development to be studied under physiological conditions with reproducibility and access to a range of developmental stages.

Aims: To investigate the emergence of cell, molecular, and functional IN phenotypes in a 16p11.2^+/- rat model.

Funding Notes

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0.
EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]
You should also ensure that two references have been send to [Email Address Removed] by the deadline using the EASTBIO Reference Form.

References

Morson, Yang, Price, Pratt (2021) Expression of Genes in the 16p11.2 Locus during Development of the Human Fetal Cerebral Cortex. Cerebral Cortex, https://doi.org/10.1093/cercor/bhab067
Yang, Booker, Clegg, Quintana Urzainqui, Sumera, Kozic, Dando, Martin Lorenzo, Herault, Kind, Price, Pratt. Identifying developing interneurons as a potential target for multiple genetic autism risk factors in human and rodent forebrain. bioRxiv 2021.06.03.446920; doi: https://doi.org/10.1101/2021.06.03.446920

Where will I study?

University of Edinburgh

One of the world''s top universities, consistently ranked in the world top 50 and placed 20th in the QS World University Rankings 2020. We provide a stimulating working, learning and teaching environment with access to excellent facilities and attract the world''s best, from Nobel Prize winning laureates to future explorers, pioneers and inventors.