Journal Article

Impaired cortico-striatal excitatory transmission triggers epilepsy

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

2019

Overview

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. Spike and wave discharge (SWD) activity is seen during absence seizures and is thought to be thalamocortical in origin. Here, the authors show that SWDs are initiated through the impaired corticostriatal excitatory transmissions onto striatal fast spiking interneurons.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 42/35 / 45/41 / 631/378/1689/178 / 631/378/3920 / 64/110 / 64/60 / 64/86 / 9/26 / 9/30 / 9/74 / 96/34 / Action Potentials - drug effects / Animals / Anticonvulsants - pharmacology / Cerebral cortex / Circuits / Convulsions & seizures / Corpus Striatum - drug effects / Corpus Striatum - metabolism / Corpus Striatum - pathology / Dioxoles - pharmacology / Discharge / Electroencephalography / Epilepsy / Epilepsy, Absence - drug therapy / Epilepsy, Absence - genetics / Epilepsy, Absence - metabolism / Epilepsy, Absence - physiopathology / Ethosuximide - pharmacology / Firing pattern / Gene Expression Regulation / Haploinsufficiency / Humanities and Social Sciences / Interneurons / Interneurons - drug effects / Interneurons - metabolism / Interneurons - pathology / Mice / Mice, Knockout / multidisciplinary / Munc18 Proteins - deficiency / Munc18 Proteins - genetics / Mutation / NAV1.2 Voltage-Gated Sodium Channel - deficiency / NAV1.2 Voltage-Gated Sodium Channel - genetics / Neocortex / Neocortex - drug effects / Neocortex - metabolism / Neocortex - pathology / Neostriatum / Neural Pathways - drug effects / Neural Pathways - metabolism / Pharmacology / Piperidines - pharmacology / Potentiation / Receptors, AMPA - genetics / Receptors, AMPA - metabolism / Science / Science (multidisciplinary) / Seizures / Seizures - genetics / Seizures - metabolism / Seizures - physiopathology / Seizures - prevention & control / Signal Transduction / Spikes / Spiking / Synaptic Transmission / Thalamus / Thalamus - drug effects / Thalamus - metabolism / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid / α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors