A human Dravet syndrome model from patient induced pluripotent stem cells

Norimichi Higurashi, Taku Uchida, Christoph Lossin, Yoshio Misumi, Yohei Okada, Wado Akamatsu, Yoichi Imaizumi, Bo Zhang, Kazuki Nabeshima, Masayuki X. Mori, Shutaro Katsurabayashi, Yukiyoshi Shirasaka, Hideyuki Okano, Shinichi Hirose

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59 Citations (Scopus)

Abstract

Background: Dravet syndrome is a devastating infantile-onset epilepsy syndrome with cognitive deficits and autistic traits caused by genetic alterations in SCN1A gene encoding the α-subunit of the voltage-gated sodium channel Nav1.1. Disease modeling using patient-derived induced pluripotent stem cells (iPSCs) can be a powerful tool to reproduce this syndrome's human pathology. However, no such effort has been reported to date. We here report a cellular model for DS that utilizes patient-derived iPSCs. Results: We generated iPSCs from a Dravet syndrome patient with a c.4933C>T substitution in SCN1A, which is predicted to result in truncation in the fourth homologous domain of the protein (p.R1645*). Neurons derived from these iPSCs were primarily GABAergic (>50%), although glutamatergic neurons were observed as a minor population (<1%). Current-clamp analyses revealed significant impairment in action potential generation when strong depolarizing currents were injected. Conclusions: Our results indicate a functional decline in Dravet neurons, especially in the GABAergic subtype, which supports previous findings in murine disease models, where loss-of-function in GABAergic inhibition appears to be a main driver in epileptogenesis. Our data indicate that patient-derived iPSCs may serve as a new and powerful research platform for genetic disorders, including the epilepsies.

Original languageEnglish
Article number19
JournalMolecular brain
Volume6
Issue number1
DOIs
Publication statusPublished - 2013 May 6

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Keywords

  • Action potential
  • Disease modeling
  • Dravet syndrome
  • Epileptogenesis
  • Gamma aminobutyric acid
  • Induced pluripotent stem cells
  • Nav1.1
  • SCN1A

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Higurashi, N., Uchida, T., Lossin, C., Misumi, Y., Okada, Y., Akamatsu, W., Imaizumi, Y., Zhang, B., Nabeshima, K., Mori, M. X., Katsurabayashi, S., Shirasaka, Y., Okano, H., & Hirose, S. (2013). A human Dravet syndrome model from patient induced pluripotent stem cells. Molecular brain, 6(1), [19]. https://doi.org/10.1186/1756-6606-6-19