Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice

Ikuo Ogiwara, Hiroyuki Miyamoto, Tetsuya Tatsukawa, Tetsushi Yamagata, Tojo Nakayama, Nafiseh Atapour, Eriko Miura, Emi Mazaki, Sara J. Ernst, Dezhi Cao, Hideyuki Ohtani, Shigeyoshi Itohara, Yuchio Yanagawa, Mauricio Montal, Michisuke Yuzaki, Yushi Inoue, Takao K. Hensch, Jeffrey L. Noebels, Kazuhiro Yamakawa

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15 Citations (Scopus)

Abstract

Mutations in the SCN2A gene encoding a voltage-gated sodium channel Nav1.2 are associated with epilepsies, intellectual disability, and autism. SCN2A gain-of-function mutations cause early-onset severe epilepsies, while loss-of-function mutations cause autism with milder and/or later-onset epilepsies. Here we show that both heterozygous Scn2a-knockout and knock-in mice harboring a patient-derived nonsense mutation exhibit ethosuximide-sensitive absence-like seizures associated with spike-and-wave discharges at adult stages. Unexpectedly, identical seizures are reproduced and even more prominent in mice with heterozygous Scn2a deletion specifically in dorsal-telencephalic (e.g., neocortical and hippocampal) excitatory neurons, but are undetected in mice with selective Scn2a deletion in inhibitory neurons. In adult cerebral cortex of wild-type mice, most Nav1.2 is expressed in excitatory neurons with a steady increase and redistribution from proximal (i.e., axon initial segments) to distal axons. These results indicate a pivotal role of Nav1.2 haplodeficiency in excitatory neurons in epilepsies of patients with SCN2A loss-of-function mutations.

Original languageEnglish
Article number96
JournalCommunications biology
Volume1
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

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    Ogiwara, I., Miyamoto, H., Tatsukawa, T., Yamagata, T., Nakayama, T., Atapour, N., Miura, E., Mazaki, E., Ernst, S. J., Cao, D., Ohtani, H., Itohara, S., Yanagawa, Y., Montal, M., Yuzaki, M., Inoue, Y., Hensch, T. K., Noebels, J. L., & Yamakawa, K. (2018). Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice. Communications biology, 1(1), [96]. https://doi.org/10.1038/s42003-018-0099-2