Understanding the neurobiology of autism in NF1 using patient derived stem cell models

Summary vAutism (or autism spectrum disorder; ASD) is a neurodevelopmental disorder characterised by debilitating impairments in social communication and restricted interests and repetitive behaviours. In most cases, the cause of autism is unknown and because of this, there are no effective treatments for autism in the general population. However, a subset of individuals (15-20%), autism occurs in children with a clinically defined syndrome which arise from a single gene disorder. This is the case in children with neurofibromatosis type 1 (NF1), an autosomal dominant disorder caused by a loss-of-function mutation in the NF1 gene. Studying a monogenic disorder with a high prevalence of autism will allow a more targeted and deeper understanding of the neurobiological mechanisms of ASD in NF1.

Project Details

Autism (or autism spectrum disorder; ASD) is a neurodevelopmental disorder characterised by debilitating impairments in social communication and restricted interests and repetitive behaviours. In most cases, the cause of autism is unknown and because of this, there are no effective treatments for autism in the general population. However, a subset of individuals (15-20%), autism occurs in children with a clinically defined syndrome which arise from a single gene disorder. This is the case in children with neurofibromatosis type 1 (NF1), an autosomal dominant disorder caused by a loss-of-function mutation in the NF1 gene. Studying a monogenic disorder with a high prevalence of autism will allow a more targeted and deeper understanding of the neurobiological mechanisms of ASD in NF1.     

Whilst animal models have traditionally been used by researchers to understand disease mechanisms, translation from animal studies to effective human clinical trials has proven difficult, including in NF1. A potential explanation for this is the inadequacy of animal models to recapitulate the complexity of the human disease state.     

This project will investigate how and why 25% of children with the genetic syndrome NF1 develop neurodevelopmental disorders such as autism. This project will use patient derived stem cell models to characterise the neuronal deficits in individuals with NF1. Specifically, human stem cell-derived brain cell networks (comprising neurons and glia) will be generated to examine the effects of NF1 mutations on neuronal development, determine how well they connect together in networks and whether they are able to function efficiently. Various drugs targeting specific pathways important in NF1 will also be used in the stem cell derived neuronal networks to determine whether they can reverse the biological abnormality in these cells. Some of the techniques that will be used in this project include stem cell culturing, differentiation of stem cells into brain cells, confocal microscopy, network activity assays, drug screening techniques, real time PCR and western blot analysis.