Absence-like seizures and their pharmacological profile in tottering-6j mice

• Published in: Biochemical and biophysical research communications 2015-07, Vol.463 (1-2), p.148-153
• Main Authors: Kim, Tae Yeon, Maki, Takehiro, Zhou, Ying, Sakai, Keita, Mizuno, Yuri, Ishikawa, Akiyoshi, Tanaka, Ryo, Niimi, Kimie, Li, Weidong, Nagano, Norihiro, Takahashi, Eiki
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - pharmacology; Antiepileptic drug; Ataxia; Ataxia - drug therapy; Ataxia - genetics; Ataxia - physiopathology; Cacna1a; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - physiology; Disease Models, Animal; Electroencephalograms; Electroencephalography; Electrophysiological Phenomena; Epilepsy, Absence - drug therapy; Epilepsy, Absence - genetics; Epilepsy, Absence - physiopathology; Ethosuximide - pharmacology; HEK293 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Neurologic Mutants; Mutant Proteins - genetics; Mutant Proteins - physiology; Mutation; Patch-Clamp Techniques; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Spike-and-wave discharge; Tottering-6j mice; Valproic Acid - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.05.050

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 Ca2+ 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. •Tottering-6j and wild-type mouse brains showed similar CaV2.1α1 expression patterns.•Tottering-6j mice showed abnormal inactivation of the Ca2+ channel current.•Tottering-6j mice exhibited absence-like seizure in EGG recordings.•Pharmacological profile in mutants is similar with that of absence seizure in humans.