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

Chad O Brown; Jarryll A Uy; Nadeem Murtaza; Elyse Rosa; Alexandria Alfonso; Biren M Dave; Savannah Kilpatrick; Annie A Cheng; Sean H White; Stephen W Scherer; Karun K Singh

doi:10.3389/fncel.2023.1239069

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

Front Cell Neurosci. 2024 Jan 16:17:1239069. doi: 10.3389/fncel.2023.1239069. eCollection 2023.

Authors

Chad O Brown^#^{1

2}, Jarryll A Uy^#^{2

3}, Nadeem Murtaza^{1

2}, Elyse Rosa¹, Alexandria Alfonso¹, Biren M Dave^{4

5}, Savannah Kilpatrick^{1

2}, Annie A Cheng², Sean H White¹, Stephen W Scherer^{4

5}, Karun K Singh^{1

2

3}

Affiliations

¹ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
² Krembil Research Institute, University Health Network, Toronto, ON, Canada.
³ Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁵ SickKids Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.

^# Contributed equally.

Abstract

SCN2A is an autism spectrum disorder (ASD) risk gene and encodes a voltage-gated sodium channel. However, the impact of ASD-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 de novo R607* truncating variant. We used Neurogenin2 to generate excitatory (glutamatergic) neurons and found that SCN2A^+/R607* and SCN2A^-/- 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 de novo truncating SCN2A variant impairs the development of human neuronal function.

Keywords: autism; dendrite; human neuron; sodium channel; synapse.

Grants and funding

Funding for the study was provided by grants from the Canadian Institutes of Health Research (CIHR), Ontario Brain Institute-POND study and the Natural Sciences and Engineering Research Council (NSERC) to KS. SS received funding from OBI-POND, Autism Speaks and CIHR. JU was awarded a fellowship from CIHR (CGS-M) and the University of Toronto Vision Science Research Program, and CB was awarded a fellowship from the McMaster University Michael G. DeGroote Institute for Pain Research and Care.