Using Drosophila to model synaptic function in NF1 autism

Neurofibromatosis type 1(NF1) is a common single gene autosomal dominant genetic disorder affecting 1 in 2500 people. Around 80% children with NF1 show leaning impairments and 45% show Autism Spectrum Disorder (ASD) symptomatology. NF1 critically regulates Ras-GTP signaling; impaired NF1 function leads to disinhibition of Ras signalling, increased GABA mediated inhibition and impairments in synaptic plasticity and function. Targeted treatments such as Simvastatin reverse the NF1 associated cognitive impairments in animal models but translational clinical trials in humans have been unsuccessful. There are no current treatments for NF1 associated social and learning impairments, which often result in lifelong social and occupational disability.
The fruitfly Drosophila has been used, by a few labs, to investigate the genetic basis of autism. The Drosophila Nf1 model shows excessive grooming behaviour that mirrors altered behaviour observed in rodent models. The aim of this proposal is to fully develop a Drosophila model of Nf1 ASD that will allow a more detailed investigation into synaptic function and cellular physiology with a view to developing new therapeutic strategies. Using nf1 mutant flies, this study will investigate whether the Nf1 mutation affects Drosophila social behaviors analogous to the ASD like phenotypes reported in humans and mice.
Social behavior of nf1 mutants versus wild type controls will be investigated using a battery of behavioural assays including acoustic communication, inter individual distance, competitive courtship, locomotor and grooming assays. Significant advantages of Drosophila over other models systems include its simple nervous system, rapid generation time, powerful genetic toolkit, low cost and availability of high throughput drug screening techniques. By studying the role of NF1 in social learning and behavior, we can uncover novel signaling pathways regulated by NF1 that may provide new therapeutic targets. Insights gained from NF1 may be applicable to more common forms of autism. This work will benefit from the well-developed NF1 ASD clinical research programme, which will provide the platform for rapid translation of the preclinical findings for patient benefit.