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The Journal of Neuroscience, November 19, 2008, 28(47):12465-12476; doi:10.1523/JNEUROSCI.2961-08.2008

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Cellular/Molecular
Rats Harboring S284L Chrna4 Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype

Gang Zhu,^1,14 * Motohiro Okada,^1,6,14 * Shukuko Yoshida,^1,7 Shinya Ueno,^3,14 Fumiaki Mori,⁴ Tomoko Takahara,⁸ Ryo Saito,⁸ Yoshiki Miura,¹⁰ Akihiro Kishi,¹¹ Masahiko Tomiyama,⁵ Akira Sato,¹² Toshio Kojima,^12,14 Goryu Fukuma,^9,14 Koichi Wakabayashi,^4,14 Koji Hase,¹³ Hiroshi Ohno,^13,14 Hiroshi Kijima,² Yukio Takano,⁸ Akihisa Mitsudome,⁹ Sunao Kaneko,^1,14 and Shinichi Hirose^9,14

Departments of ¹Neuropsychiatry, ²Pathology and Bioscience, ³Neurophysiology, ⁴Neuropathology, and ⁵Neurological Science, Institute of Brain Science, Graduate School of Medicine, Hirosaki University, Hirosaki 036-8562, Japan, ⁶Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu 514-8507, Japan, ⁷Institute of Neuroscience and Molecular Biology, Shibata IRIKA, Hirosaki 036-8084, Japan, ⁸Department of Pharmacology, Faculty of Pharmaceutical Sciences, and ⁹Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan, ¹⁰Pharmacology Research Laboratories, Dainippon Sumitomo Pharmacy Company, Osaka 541-8524, Japan, ¹¹Discovery Research Laboratories III, Ono Pharmaceutical Company, Osaka 541-8564, Japan, ¹²RIKEN Genomic Sciences Center and ¹³RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan, and ¹⁴The Epilepsy Genetic Study Group,Hirosaki 036-8562 Japan

Correspondence should be addressed to Shinichi Hirose, Department of Pediatrics, Fukuoka University, 45-1, 7-chome, Nanakuma, Jonan-ku Fukuoka 814-0180, Japan. Email: hirose{at}fukuoka-u.ac.jp

Mutations of genes encoding 4, β2, or 2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of nAChR [neuronal nicotinic ACh (acetylcholine) receptor] cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and are characterized by three distinct seizure phenotypes: "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering." We generated transgenic rat strains that harbor a missense mutation S284L, which had been identified in CHRNA4 in NFLE. The transgenic rats were free of biological abnormalities, such as dysmorphology in the CNS, and behavioral abnormalities. The mRNA level of the transgene (mutant Chrna4) was similar to the wild type, and no distorted expression was detected in the brain. However, the transgenic rats showed epileptic seizure phenotypes during slow-wave sleep (SWS) similar to those in NFLE exhibiting three characteristic seizure phenotypes and thus fulfilled the diagnostic criteria of human NFLE. The therapeutic response of these rats to conventional antiepileptic drugs also resembled that of NFLE patients with the S284L mutation. The rats exhibited two major abnormalities in neurotransmission: (1) attenuation of synaptic and extrasynaptic GABAergic transmission and (2) abnormal glutamate release during SWS. The currently available genetically engineered animal models of epilepsy are limited to mice; thus, our transgenic rats offer another dimension to the epilepsy research field.

Key words: epilepsy; acetylcholine receptor; AChR; GABAergic modulation; glutamate; transgenic; transmission

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Received June 20, 2008; revised Sept. 16, 2008; accepted Sept. 19, 2008.

Correspondence should be addressed to Shinichi Hirose, Department of Pediatrics, Fukuoka University, 45-1, 7-chome, Nanakuma, Jonan-ku Fukuoka 814-0180, Japan. Email: hirose{at}fukuoka-u.ac.jp

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