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bioRxiv · 10.1101/2021.09.14.460368

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

Brown, C. O.·Uy, J.·Murtaza, N.·Rosa, E.·Afonso, A.·Xing, S.·Dave, B. M.·Kilpatrick, S.·Cheng, A. A.·White, S. H.·Scherer, S. W.·Lu, Y.·Singh, K. K.
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Abstract

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of autism-associated SCN2A de novo variants on human neuron development is unknown. We studied SCN2A using isogenic SCN2A-/- induced pluripotent stem cells (iPSCs), and patient-derived iPSCs harboring a p.R607* or a C-terminal p.G1744* de novo truncating variant. We used Neurogenin2 to generate excitatory glutamatergic neurons and found that SCN2A+/p.R607* and SCN2A-/- neurons displayed a reduction in synapse formation and excitatory synaptic activity using multielectrode arrays and electrophysiology. However, the p.G1744* variant, which leads to early-onset seizures in addition to ASD, altered action-potential dynamics but not synaptic activity. Proteomic and functional analysis of SCN2A+/p.R607* neurons revealed defects in neuronal morphology and bioenergetic pathways, which were not present in SCN2A+/p.G1744* neurons. Our study reveals that SCN2A de novo variants can have differential impact on human neuron function and signaling. HIGHTLIGHTS- Isogenic SCN2A-/- neurons display intrinsic hyperexcitability and impaired excitatory synapse function - SCN2A+/p.R607* variant reduces excitatory synapse function in patient neurons - C-terminal SCN2A+/p.G1744* variant enhances action potential properties but not synaptic transmission in patient neurons - SCN2A+/p.R607* variant display impacts on morphological and bioenergetic signaling networks through proteomic and functional analysis eTOC- Brown et al. examined Autism-associated SCN2A variants using patient-derived iPSC NGN2-neurons. They discover that genetic variants differentially impact neuronal development and synaptic function, and highlight neuronal and bioenergetic signaling networks underlying SCN2A loss-of-function.

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Brown, C. O., Uy, J., Murtaza, N., Rosa, E., Afonso, A., Xing, S., Dave, B. M., Kilpatrick, S., Cheng, A. A., White, S. H., Scherer, S. W., Lu, Y., Singh, K. K.. 2021-09-15. Disruption of the autism-associated gene SCN2A alters synaptic development and neuronal signaling in patient iPSC-glutamatergic neurons. https://doi.org/10.1101/2021.09.14.460368

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