Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons

Abstract

<i>SCN2A</i> is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-associated SCN2A <i>de novo</i> variants on human neuron development is unknown. We studied SCN2A using isogenic <i>SCN2A</i>^-/- induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a <i>de novo</i> R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that <i>SCN2A</i>^{+/<i>R</i>607*} and <i>SCN2A</i>^-/- neurons displayed a reduction in synapse formation and excitatory synaptic activity. We found differential impact on actional potential dynamics and neuronal excitability that reveals a loss-of-function effect of the R607* variant. Our study reveals that a <i>de novo</i> truncating <i>SCN2A</i> variant impairs the development of human neuronal function.