Impaired cortico-striatal excitatory transmission triggers epilepsy

Hiroyuki Miyamoto, Tetsuya Tatsukawa, Atsushi Shimohata, Tetsushi Yamagata, Toshimitsu Suzuki, Kenji Amano, Emi Mazaki, Matthieu Raveau, Ikuo Ogiwara, Atsuko Oba-Asaka, Takao K. Hensch, Shigeyoshi Itohara, Kenji Sakimura, Kenta Kobayashi, Kazuto Kobayashi and Kazuhiro Yamakawa ()
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Hiroyuki Miyamoto: RIKEN Center for Brain Science, Wako
Tetsuya Tatsukawa: RIKEN Center for Brain Science, Wako
Atsushi Shimohata: RIKEN Center for Brain Science, Wako
Tetsushi Yamagata: RIKEN Center for Brain Science, Wako
Toshimitsu Suzuki: RIKEN Center for Brain Science, Wako
Kenji Amano: RIKEN Center for Brain Science, Wako
Emi Mazaki: RIKEN Center for Brain Science, Wako
Matthieu Raveau: RIKEN Center for Brain Science, Wako
Ikuo Ogiwara: RIKEN Center for Brain Science, Wako
Atsuko Oba-Asaka: The University of Tokyo Institutes for Advanced Study
Takao K. Hensch: The University of Tokyo Institutes for Advanced Study
Shigeyoshi Itohara: RIKEN Center for Brain Science, Wako
Kenji Sakimura: Niigata University
Kenta Kobayashi: National Institute for Physiological Sciences
Kazuto Kobayashi: Fukushima Medical University School of Medicine
Kazuhiro Yamakawa: RIKEN Center for Brain Science, Wako

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.

Date: 2019
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DOI: 10.1038/s41467-019-09954-9

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