Project 44.2: Deciphering mechanisms and biomarkers of autism through mutations in the SHANK3 gene: A Translational approach

Autism is a pervasive neurodevelopmental syndrome characterized by deficits in social reciprocity and

communication, and presence of repetitive behaviours. Given the worldwide increase in autism, effective

interventions are urgently needed. This is however hampered by our poor understanding of causal

mechanisms, mainly due to autism's heterogeneity in aetiology. In that respect, single-gene forms of

autism, such as the Phelan McDermid Syndrome (PMS) caused by a mutation in the SHANK3 gene, are

better suited to elucidate the pathophysiology of autism.

In our translational research, human and rodent studies are combined to elucidate the neurobiological

underpinnings of autism. We offer a PhD opportunity to join our team and work with humans and rodents

to examine the biology associated with SHANK3 gene mutations. We use MRI as a translational tool to

examine the brain structure, function and biochemistry. We aim to define the brain systems involved in

PMS/autism in our patient populations and then establish whether these signatures can be recapitulated

in rodents carrying the same mutation. This back-translation into animal models coupled with cutting-

edge methods (e.g. 3D imaging in transparent brains (CLARITY), optogenetics, electrophysiology) will

allow us to confirm the cellular basis of brain deficits and generate novel treatment targets. In the first

year the student will learn technical skills and begin to acquire MRI data. In the second and third years,

they will examine in more detail the neurobiology of SHANK3 mutation. This multidisciplinary project

provides an outstanding array of skills and a potential to rapidly impact upon our understanding of autism.