Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor

• Published in: Neuroscience research 2015-11, Vol.100, p.46-54
• Main Authors: Shiba, Yuko, Mori, Fumiaki, Yamada, Junko, Migita, Keisuke, Nikaido, Yoshikazu, Wakabayashi, Koichi, Kaneko, Sunao, Okada, Motohiro, Hirose, Shinichi, Ueno, Shinya
• Format: Article
• Language: English
• Subjects: Animals; Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); Brain - metabolism; Brain - physiopathology; Disease Models, Animal; Electroencephalography; Epilepsy; Epilepsy - chemically induced; Epilepsy - genetics; Epilepsy - physiopathology; Epilepsy, Frontal Lobe - genetics; Epilepsy, Frontal Lobe - metabolism; Epilepsy, Frontal Lobe - physiopathology; Male; Mutation, Missense; Nicotine - pharmacology; Nicotinic acetylcholine receptor (nAChR) mutation; Protein Subunits; Rats; Rats, Transgenic; Receptors, Nicotinic - genetics; Receptors, Nicotinic - metabolism; Seizures; Sensorimotor Cortex - metabolism; Transgenic rat; β2-Subunit
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2015.06.003

•Rats with a missense mutation in the nicotinic receptor β2 subunit were generated.•V286L-TG showed spontaneous epileptic seizures, similar to human ADNFLE.•V286L-TG rats demonstrated hypersensitivity to nicotine administration.•V286L-TG may cause an imbalance of excitation versus inhibition leading to seizures. 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.