It's a Storm, It's a Gale: Epilepsy Initiation From the Corticostriatal Circuit.

Abstract

Impaired Cortico-Striatal Excitatory Transmission Triggers Epilepsy Miyamoto H, Tatsukawa T, Shimohata A, Yamagata T, Suzuki T, Amano K, Mazaki E, Raveau M, Ogiwara I, Oba-Asaka A, Hensch TK, Itohara S, Sakimura K, Kobayashi K, Kobayashi K, Yamakawa, K, Nature Communications. 2019;10:1917; https://doi.org/10.1038/s41467-019-09954-9. 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 corticostriatal but not corticothalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). Fast-spiking interneurons 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 corticostriatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired corticostriatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice.