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: Yuko Shiba, Fumiaki Mori, Junko Yamada, Keisuke Migita, Yoshikazu Nikaido, Koichi Wakabayashi, Sunao Kaneko, Motohiro Okada, Shinichi Hirose, Shinya Ueno
• Journal: Neuroscience research (Neurosci Res) Vol. 100 Pg. 46-54 (Nov 2015) ISSN: 1872-8111 [Electronic] Ireland
• PMID: 26091610 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Chemical References

• Protein Subunits
• Receptors, Nicotinic
• nicotinic receptor beta2
• Nicotine

Topics

• Animals
• Brain (metabolism, physiopathology)
• Disease Models, Animal
• Electroencephalography
• Epilepsy (chemically induced, genetics, physiopathology)
• Epilepsy, Frontal Lobe (genetics, metabolism, physiopathology)
• Male
• Mutation, Missense
• Nicotine (pharmacology)
• Protein Subunits
• Rats
• Rats, Transgenic
• Receptors, Nicotinic (genetics, metabolism)
• Sensorimotor Cortex (metabolism)