Impaired cortico-striatal excitatory transmission triggers epilepsy

Hiroyuki Miyamoto,Kenta Kobayashi,Takao K Hensch,Atsushi Shimohata,Ikuo Ogiwara,Kenji Amano,Shigeyoshi Itohara,Atsuko Oba-Asaka,Kazuto Kobayashi,Toshimitsu Suzuki,Tetsushi Yamagata,Kazuhiro Yamakawa,Kenji Sakimura,Matthieu Raveau,Emi Mazaki,Tetsuya Tatsukawa

doi:10.1038/s41467-019-09954-9

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.

Highlights

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, the circuit basis remains elusive
Contrary to the previous proposal of the basal ganglia as merely a modulator of spike-and-wave discharges (SWDs) primarily produced by thalamocortical circuits[26,27,28], we here show that impairments in cortico-striatal, rather than cortico-thalamic, pathways trigger SWDs in Stxbp1+/− and Scn2a+/− mice using multiple experimental approaches
Similar to other rodent models of absence epilepsy[19,20] and Scn2a+/− mice[15], Stxbp[1] knockout mice showed synchronous bilateral cortical SWDs during behavioral quiescence (Fig. 1a) and effective suppression of SWDs following ethosuximide administration (Fig. 1b), they were regarded as experiencing absence seizures

Summary

Introduction

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, the circuit basis remains elusive. 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. FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. 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 Stxbp[1] and Scn2a haplodeficient mice. Contrary to the previous proposal of the basal ganglia as merely a modulator of SWDs primarily produced by thalamocortical circuits[26,27,28], we here show that impairments in cortico-striatal, rather than cortico-thalamic, pathways trigger SWDs in Stxbp1+/− and Scn2a+/− mice using multiple experimental approaches

Methods

Results

Conclusion