Investigating interneuron dysfunction in a human stem cell model of amytrophic lateral sclerosis and frontotemporal dementia

Interneurons play a critical role in the nervous system by regulating the balance of excitability and correct timing of circuit activity. Interneuron dysfunction and/or degeneration is therefore associated with many neurological diseases. This project will investigate interneuronal dysfunction associated with amytrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Multiple lines of evidence indicate that interneurons are dysfunctional and, indeed degenerate, in ALS and FTD, giving rise to circuit or network hypexcitability that is thought to promote excitotoxicity leading to degeneration. However, whether interneuronal dysfunction is present in patients who harbour the C9ORF72 repeat expansion, the most common genetic cause of both ALS and FTD, remains unknown.

To address this question, the project will involve an interdisciplinary approach that will principally combine in vitro human stem cell technology and electrophysiological methods. The student will be trained to generate in vitro populations of interneurons derived from C9ORF72 repeat expansion patient induced pluripotent stem cells, from which they will be also trained to make patch-clamp electrophysiology recordings in order to determine physiological dysfunction. This project will also take advantage of experimental tools involving gene-editing, immunocytochemistry, pharmacology and multi-electrode array electrophysiology.

The project will be performed in the laboratories of Dr Matthew Livesey (principal supervisor) and Dr Laura Ferraiuolo (secondary supervisor), who are based in Sheffield Institute for Translational Neuroscience (SITraN), which has an established international reputation for ALS research.