Nav1.2 haplodeficiency in excitatory neurons causes absence-like seizures in mice PMID: 30175250

ADC Targets in Oncology

2026-04-10

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

Commun Biol. 2018:1:96. doi: 10.1038/s42003-018-0099-2.

Ikuo Ogiwara ¹ ² , Hiroyuki Miyamoto ¹ ³ ⁴ , Tetsuya Tatsukawa ¹ , Tetsushi Yamagata ¹ , Tojo Nakayama ¹ ⁵ ⁶ , Nafiseh Atapour ¹ ³ ⁷ , Eriko Miura ⁸ , Emi Mazaki ¹ , Sara J Ernst ⁹ ¹⁰ , Dezhi Cao ¹¹ ¹² , Hideyuki Ohtani ¹¹ , Shigeyoshi Itohara ¹³ ¹⁴ , Yuchio Yanagawa ¹⁵ ¹⁶ , Mauricio Montal ¹⁷ , Michisuke Yuzaki ⁸ , Yushi Inoue ¹¹ , Takao K Hensch ³ ¹⁸ ¹⁹ , Jeffrey L Noebels ⁹ ¹⁰ ²⁰ , Kazuhiro Yamakawa ²¹

Affiliations

1. Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
2. Department of Physiology, Nippon Medical School, Tokyo, 113-8602, Japan.
3. Laboratory for Neuronal Circuit Development, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
4. PRESTO, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
5. Department of Pediatrics, Tohoku University School of Medicine, Sendai, 980-8574, Japan.
6. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
7. Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, University of Melbourne, Parkville, VIC, 3050, Australia.
8. Department of Physiology, School of Medicine, Keio University, Tokyo, 160-8582, Japan.
9. Department of Neurology, Baylor College of Medicine, Houston, TX, 77030, USA.
10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
11. National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka, 420-8688, Japan.
12. Neurology Department, Shenzhen Children's Hospital, 518026, Guangdong, China.
13. Laboratory for Behavioral Genetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan.
14. FIRST, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
15. Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.
16. CREST, Japan Science and Technology Agency, Saitama, 332-0012, Japan.
17. Section of Neurobiology, Division of Biological Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
18. Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA, 02138, USA.
19. Department of Neurology, FM Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
20. Department of Neuroscience, Baylor College of Medicine, Houston, TX, 77030, USA.
21. Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan. [email protected].

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.