Dataset Information

Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.

ABSTRACT: 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.

SUBMITTER: Ogiwara I

PROVIDER: S-EPMC6115194 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.

Ogiwara Ikuo I Miyamoto Hiroyuki H Tatsukawa Tetsuya T Yamagata Tetsushi T Nakayama Tojo T Atapour Nafiseh N Miura Eriko E Mazaki Emi E Ernst Sara J SJ Cao Dezhi D Ohtani Hideyuki H Itohara Shigeyoshi S Yanagawa Yuchio Y Montal Mauricio M Yuzaki Michisuke M Inoue Yushi Y Hensch Takao K TK Noebels Jeffrey L JL Yamakawa Kazuhiro K

Communications biology 20180719

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 associat ...[more]

PMID: 30175250

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Dataset Information

Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.

Publications

Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice.

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