title: Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor.
abstract: We generated a transgenic rat strain with a missense mutation in V286L (V286L-TG), in the gene encoding the neuronal nicotinic acetylcholine receptor β2 subunit (CHRNB2) found in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To confirm that V286L-TG rats exhibit seizures similar to those observed in humans, gene expression patterns and behavioral phenotypes were analyzed. In situ hybridization using a V286L Chrnb2-selective probe indicated that the transgene was expressed at higher levels in the cortex, hippocampus, and cerebellum of V286L-TG than wild-type littermates (non-TG). Spontaneous epileptic seizures with ictal discharges in electroencephalograms were detected in 45% of V286L-TG rats and the frequency of seizures was 0.73 times a week. This seizure type is similar to "paroxysmal arousals" that are observed in human ADNFLE. V286L-TG rats displayed nicotine-induced abnormal motor activity including seizures in comparison to non-TGs. Response time following nicotine administration occurred faster in V286L-TG than in non-TG rats. V286L-TG rats demonstrated spontaneous epileptic seizures, which are similar to human ADNFLE, and also showed a higher sensitivity to nicotine administration. Thus, the V286L-TG rat model could be a valuable tool for developing novel mechanism-driven treatment strategies for epilepsy and provide a better understanding of ADNFLE.
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: shibako@hirosaki-u.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shiba
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: neuropal@hirosaki-u.ac.jp.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.affiliation: Department of Biomedical Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki 036-8564, Japan. Electronic address: jyamada@hirosaki-u.ac.jp.
authors.forename: Junko
authors.initials: J
authors.lastname: Yamada
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: migitak@hirosaki-u.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Migita
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: ynikaido@hirosaki-u.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nikaido
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: koichi@hirosaki-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
authors.affiliation: Department of Neuropsychiatry, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan; North Tohoku Epilepsy Center, Hachinohe 031-0813, Japan. Electronic address: sk@epigene.org.
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Psychiatry, Mie University Graduate School of Medicine, Tsu 514-8507, Japan. Electronic address: okadamot@clin.medic.mie-u.ac.jp.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Pediatrics, Fukuoka University, Fukuoka 814-0180, Japan. Electronic address: hirose@fukuoka-u.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
authors.affiliation: Department of Neurophysiology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan. Electronic address: shinyau@hirosaki-u.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D017034:Epilepsy, Frontal Lobe / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D020125:Mutation, Missense; D009538:Nicotine / Q000494:pharmacology; D021122:Protein Subunits; D051381:Rats; D055647:Rats, Transgenic; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D066191:Sensorimotor Cortex / Q000378:metabolism
chemical_list: D009538:Nicotine; D021122:Protein Subunits; D011978:Receptors, Nicotinic
keywords: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); Epilepsy; Nicotinic acetylcholine receptor (nAChR) mutation; Seizures; Transgenic rat; β2-Subunit