Using Drosophila to model synaptic dysfunction and behaviour in NF1-ASD

Abstract

Autism spectrum disorder (ASD) affects 1 – 2 % of the overall population and is characterised by the presence of social communication deficits alongside repetitive behaviours and restricted interests. Currently, there are no treatments available that effectively and consistently target these core symptom domains, largely attributed to a poor understanding of the underlying mechanisms. Accordingly, this project aims to investigate (a) the effect of loss of ASD-associated NF1 expression on synaptic activity, and how this might impact behaviour, (b) the underlying mechanisms by which this may occur, and (c) the application of a Drosophila model of NF1 to genetic and pharmacological screens. Chapter 2 details the development of an assay in which high-frequency bursts of activity, as detected by the TriKinetics Drosophila Activity Monitor system, are used as a proxy for excessive grooming behaviour in a Drosophila model of NF1. This provides the basis for a subsequent pharmacological screen to identify compounds that may have therapeutic potential in treating repetitive behaviours in ASD. However, no compound with consistent efficacy is identified. Chapter 3 investigates the role of NF1 in regulating synaptic function at the larval neuromuscular junction (NMJ), showing that loss of NF1 expression results in changes to transmission indicative of neuronal hyperexcitability, consistent with an excitation/inhibition imbalance hypothesis of ASD. Such changes likely arise via excessive Ras/MAPK activity and are associated with hypersensitivity to a mechanical stimulus, which is proposed to mirror the sensory sensitivity abnormalities characteristic of ASD. Chapter 4 then examines whether these larval phenotypes may be applied to genetic and pharmacological screens for the identification of novel NF1-ASD mechanisms and therapies. An electrophysiological screen identifies several genes as possible NF1 interactors, although their differential expression in the NF1P1 homozygous mutant could not be confirmed. Thus, their involvement in NF1-dependent transmission remains unclear. On the other hand, a pharmacological screen for compounds able to improve tactile hypersensitivity in NF1P1 larvae identified two compounds, simvastatin and BMS204352, as able to reduce, but not fully rescue, the phenotype.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Richard Baines (Supervisor), Dafydd Evans (Supervisor) & Shruti Garg (Supervisor)