論文 - 詳細
| RRC ID | 55775 |
|---|---|
| 著者 | 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. |
| タイトル | Impaired cortico-striatal excitatory transmission triggers epilepsy. |
| ジャーナル | Nat Commun |
| 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. |
| 巻・号 | 10(1) |
| ページ | 1917 |
| 公開日 | 2019-4-23 |
| DOI | 10.1038/s41467-019-09954-9 |
| PII | 10.1038/s41467-019-09954-9 |
| PMID | 31015467 |
| PMC | PMC6478892 |
| MeSH | Action Potentials / drug effects Animals Anticonvulsants / pharmacology Corpus Striatum / drug effects Corpus Striatum / metabolism* Corpus Striatum / pathology Dioxoles / pharmacology Electroencephalography Epilepsy, Absence / drug therapy Epilepsy, Absence / genetics Epilepsy, Absence / metabolism Epilepsy, Absence / physiopathology Ethosuximide / pharmacology Gene Expression Regulation Haploinsufficiency Interneurons / drug effects Interneurons / metabolism Interneurons / pathology Mice Mice, Knockout Munc18 Proteins / deficiency Munc18 Proteins / genetics* NAV1.2 Voltage-Gated Sodium Channel / deficiency NAV1.2 Voltage-Gated Sodium Channel / genetics* Neocortex / drug effects Neocortex / metabolism* Neocortex / pathology Neural Pathways / drug effects Neural Pathways / metabolism Piperidines / pharmacology Receptors, AMPA / genetics Receptors, AMPA / metabolism Seizures / genetics* Seizures / metabolism Seizures / physiopathology Seizures / prevention & control Signal Transduction Synaptic Transmission* Thalamus / drug effects Thalamus / metabolism |
| IF | 11.878 |
| 引用数 | 8 |
| リソース情報 | |
| ラット | GAERS/Mave (strainID=557) |