title: Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.
abstract: Mutations of genes encoding alpha4, beta2, or alpha2 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.
authors.affiliation: Department of Neuropsychiatry, Institute of Brain Science, Graduate School of Medicine, Hirosaki University, Hirosaki 036-8562, Japan.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhu
authors.forename: Motohiro
authors.initials: M
authors.lastname: Okada
authors.forename: Shukuko
authors.initials: S
authors.lastname: Yoshida
authors.forename: Shinya
authors.initials: S
authors.lastname: Ueno
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takahara
authors.forename: Ryo
authors.initials: R
authors.lastname: Saito
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Miura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kishi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tomiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Sato
authors.forename: Toshio
authors.initials: T
authors.lastname: Kojima
authors.forename: Goryu
authors.initials: G
authors.lastname: Fukuma
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Koji
authors.initials: K
authors.lastname: Hase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kijima
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takano
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mitsudome
authors.forename: Sunao
authors.initials: S
authors.lastname: Kaneko
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D017034:Epilepsy, Frontal Lobe / Q000178:diet therapy / Q000235:genetics* / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006358:Hot Temperature / Q000009:adverse effects; D066298:In Vitro Techniques; D007930:Leucine / Q000235:genetics*; D016253:Microscopy, Immunoelectron; D009043:Motor Activity / Q000235:genetics; D009048:Motor Skills / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D010433:Pentylenetetrazole / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D055647:Rats, Transgenic; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D012694:Serine / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D007930:Leucine; D018377:Neurotransmitter Agents; D009538:Nicotine; D010433:Pentylenetetrazole; D011978:Receptors, Nicotinic; D012694:Serine; D005680:gamma-Aminobutyric Acid