Uncovering the Functional Link Between SHANK3 Deletions and Deficiency in Neurodevelopment Using iPSC-Derived Human Neurons

mutations, including deletions, have been associated with autism spectrum disorders (ASD). However, the effects of loss of function on neurodevelopment remain poorly understood. Here we generated human induced pluripotent stem cells (iPSC) , followed by neuro-differentiation and lentivirus-mediated shRNA expression to evaluate how knockdown affects the neurodevelopmental process at multiple time points (up to 4 weeks). We found that knockdown impaired both early stage of neuronal development and mature neuronal function, as demonstrated by a reduction in neuronal soma size, growth cone area, neurite length and branch numbers. Notably, electrophysiology analyses showed defects in excitatory and inhibitory synaptic transmission. Furthermore, transcriptome analyses revealed that multiple biological pathways related to neuron projection, motility and regulation of neurogenesis were disrupted in cells with knockdown. In conclusion, utilizing a human iPSC-based neural induction model, this study presented combined morphological, electrophysiological and transcription evidence that support that as an intrinsic, cell autonomous factor that controls cellular function development in human neurons.