Journal
FASEB JOURNAL
Volume 33, Issue 4, Pages 5287-5299Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201801110RR
Keywords
neurogenin; induced neuronal network; GABAergic; SCN2A
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Funding
- Stanley Center for Psychiatric Research
- U.S. National Institutes of Health, National Institute of Mental Health [R21 MH099448-02, R01 MH115045-01]
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Overexpression of mouse neurogenin (Neurog)2 alone or in combination with mouse Neurog2/1 in human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can rapidly produce high-yield excitatory neurons. Here, we report a detailed characterization of human neuronal networks induced by the expression of human NEUROG2 together with human NEUROG2/1 in hESCs using molecular, cellular, and electrophysiological measurements over 60 d after induction. Both excitatory synaptic transmission and network firing activity increased over time. Strikingly, inhibitory synaptic transmission and GABAergic cells were identified from NEUROG2/1 induced neurons (iNs). To illustrate the application of such iNs, we demonstrated that the heterozygous knock out of SCN2A, whose loss-of-function mutation is strongly implicated in autism risk, led to a dramatic reduction in network activity in the NEUROG2/1 iNs. Our findings not only extend our understanding of the NEUROG2/1-induced human neuronal network but also substantiate NEUROG2/1 iNs as an in vitro system for modeling neuronal and functional deficits on a human genetic background.
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