The role of Synaptic Genes NRXN1 and SHANK3 in Autism: an induced pluripotent stem cell study

Abstract

Autism is a complex neurodevelopmental condition with hundreds of genes associated with its pathophysiology. A number of autism related genes have been reported to be strongly associated with the structural or functional aspects of neuronal connections or synapses. However, it is poorly understood how the loss of function of these synaptic genes contribute to the neuronal morphology, network physiology and atypical communication between brain cells.

This thesis aims to first establish and characterise an induced pluripotent cell (iPSC) derived neuronal model suitable for studying autism related synaptic genes. Secondly, it aims to study the effect of pre-synaptic NRXN1 and post-synaptic SHANK3 deletions on neuronal morphology and synaptic network activity.

The first hypothesis of this thesis is that iNeurons derived by NGN2 forward programming approach would express autism related genes, post synaptic density molecules, synaptic receptors and demonstrate mature electrophysiological activity relevant for studying autism related functional phenotypes, within four weeks of neuronal induction. The second hypothesis is that iNeurons with deletions in NRXN1 or SHANK3 derived from individuals with autism would show altered morphological and electrophysiological cellular phenotypes.

This study proposes a novel in vitro model for generating more homogenous and functional neurons compared to the existing methods adopted in the field of autism research. It has been exemplified that the effect mutations in synaptic genes such as NRXN1 and SHANK3 on mature cellular phenotypes can be studied using iNeurons. Further research is needed for technological fine-tuning to establish a robust scalable cell-based platform that would potentially be useful to investigate cellular phenotypes caused by anomalies in any autism risk gene and better understand the pathophysiology of neurodevelopmental conditions.