||Spontaneous epileptic seizures in transgenic rats harboring a human ADNFLE missense mutation in the β2-subunit of the nicotinic acetylcholine receptor
ヒト常染色体優性夜間前頭葉てんかん由来ニコチン性アセチルコリン受容体 β2 サブユニット変異ラットの自発性発作
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 situhybridization 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 thefrequency 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 innon-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.