Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice
| Autor: | Kazuhiro Yamakawa, Ikuo Ogiwara, Mauricio Montal, Shigeyoshi Itohara, Tojo Nakayama, Sara J. Ernst, Hideyuki Ohtani, Yuchio Yanagawa, Emi Mazaki, Dezhi Cao, Tetsuya Tatsukawa, Eriko Miura, Michisuke Yuzaki, Yushi Inoue, Hiroyuki Miyamoto, Nafiseh Atapour, Takao K. Hensch, Jeffrey L. Noebels, Tetsushi Yamagata |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Nonsense mutation Medicine (miscellaneous) Hippocampal formation Biology Inhibitory postsynaptic potential medicine.disease Axon initial segment Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Epilepsy 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure lcsh:Biology (General) Cerebral cortex NAV1 medicine Excitatory postsynaptic potential General Agricultural and Biological Sciences Neuroscience lcsh:QH301-705.5 030217 neurology & neurosurgery |
| Zdroj: | Communications Biology, Vol 1, Iss 1, Pp 1-16 (2018) |
| ISSN: | 2399-3642 |
| Popis: | Mutations in the SCN2A gene encoding a voltage-gated sodium channel Nav1.2 are associated with epilepsies, intellectual disability, and autism. SCN2A gain-of-function mutations cause early-onset severe epilepsies, while loss-of-function mutations cause autism with milder and/or later-onset epilepsies. Here we show that both heterozygous Scn2a-knockout and knock-in mice harboring a patient-derived nonsense mutation exhibit ethosuximide-sensitive absence-like seizures associated with spike-and-wave discharges at adult stages. Unexpectedly, identical seizures are reproduced and even more prominent in mice with heterozygous Scn2a deletion specifically in dorsal-telencephalic (e.g., neocortical and hippocampal) excitatory neurons, but are undetected in mice with selective Scn2a deletion in inhibitory neurons. In adult cerebral cortex of wild-type mice, most Nav1.2 is expressed in excitatory neurons with a steady increase and redistribution from proximal (i.e., axon initial segments) to distal axons. These results indicate a pivotal role of Nav1.2 haplodeficiency in excitatory neurons in epilepsies of patients with SCN2A loss-of-function mutations. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|