title: Absence-like seizures and their pharmacological profile in tottering-6j mice.
abstract: We previously showed that recessive ataxic tottering-6j mice carried a base substitution (C-to-A) in the consensus splice acceptor sequence linked to exon 5 of the α1 subunit of the Cav2.1 channel gene (Cacna1a), resulting in the skipping of exon 5 and deletion of part of the S4-S5 linker, S5, and part of the S5-S6 linker in domain I of the α1 subunit of the Cav2.1 channel. However, the electrophysiological and pharmacological consequences of this mutation have not previously been investigated. Upon whole-cell patch recording of the recombinant Cav2.1 channel in heterologous reconstitution expression systems, the mutant-type channel exhibited a lower recovery time after inactivation of Ca(2+) channel current, without any change in peak current density or the current-voltage relationship. Tottering-6j mice exhibited absence-like seizures, characterized by bilateral and synchronous 5-8 Hz spike-and-wave discharges on cortical and hippocampal electroencephalograms, concomitant with sudden immobility and staring. The pharmacological profile of the seizures was similar to that of human absence epilepsy; the seizures were inhibited by ethosuximide and valproic acid, but not by phenytoin. Thus, the tottering-6j mouse is a useful model for studying Cav2.1 channel functions and Cacna1a-related diseases, including absence epilepsy.
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, Saitama, 351-0198, Japan.
authors.forename: Tae Yeon
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Maki
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Mizuno
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ishikawa
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, Saitama, 351-0198, Japan.
authors.forename: Kimie
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.affiliation: Sleep Science Laboratories, HAMRI Co. Ltd., Ibaraki, 306-0128, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nagano
authors.affiliation: Research Resources Center, RIKEN Brain Science Institute, Saitama, 351-0198, Japan; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China. Electronic address: etakahashi@brain.riken.jp.
authors.forename: Eiki
authors.initials: E
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001259:Ataxia / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D055724:Electrophysiological Phenomena; D004832:Epilepsy, Absence / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D005013:Ethosuximide / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D020864:Calcium Channels, N-Type; D005013:Ethosuximide; D050505:Mutant Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014635:Valproic Acid
keywords: Antiepileptic drug; Ataxia; Cacna1a; Electroencephalograms; Spike-and-wave discharge; Tottering-6j mice