Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype

Gang Zhu, Motohiro Okada, Shukuko Yoshida, Shinya Ueno, Fumiaki Mori, Tomoko Takahara, Ryo Saito, Yoshiki Miura, Akihiro Kishi, Masahiko Tomiyama, Akira Sato, Toshio Kojima, Goryu Fukuma, Koichi Wakabayashi, Kouji Hase, Hiroshi Ohno, Hiroshi Kijima, Yukio Takano, Akihisa Mitsudome, Sunao Kaneko & 1 others Shinichi Hirose

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Mutations of genes encoding α4, β2, or α2 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.

Original languageEnglish
Pages (from-to)12465-12476
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number47
DOIs
Publication statusPublished - 2008 Nov 19
Externally publishedYes

Fingerprint

Frontal Lobe Epilepsy
Transgenic Rats
Phenotype
Mutation
Epilepsy
Sleep
Seizures
Genetically Modified Animals
Dystonia
Nicotinic Receptors
Missense Mutation
Arousal
Transgenes
Synaptic Transmission
Anticonvulsants
Glutamic Acid
Animal Models
Messenger RNA
Brain
Research

Keywords

  • Acetylcholine receptor
  • AChR
  • Epilepsy
  • GABAergic modulation
  • Glutamate
  • Transgenic
  • Transmission

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. / Zhu, Gang; Okada, Motohiro; Yoshida, Shukuko; Ueno, Shinya; Mori, Fumiaki; Takahara, Tomoko; Saito, Ryo; Miura, Yoshiki; Kishi, Akihiro; Tomiyama, Masahiko; Sato, Akira; Kojima, Toshio; Fukuma, Goryu; Wakabayashi, Koichi; Hase, Kouji; Ohno, Hiroshi; Kijima, Hiroshi; Takano, Yukio; Mitsudome, Akihisa; Kaneko, Sunao; Hirose, Shinichi.

In: Journal of Neuroscience, Vol. 28, No. 47, 19.11.2008, p. 12465-12476.

Research output: Contribution to journalArticle

Zhu, G, Okada, M, Yoshida, S, Ueno, S, Mori, F, Takahara, T, Saito, R, Miura, Y, Kishi, A, Tomiyama, M, Sato, A, Kojima, T, Fukuma, G, Wakabayashi, K, Hase, K, Ohno, H, Kijima, H, Takano, Y, Mitsudome, A, Kaneko, S & Hirose, S 2008, 'Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype', Journal of Neuroscience, vol. 28, no. 47, pp. 12465-12476. https://doi.org/10.1523/JNEUROSCI.2961-08.2008
Zhu, Gang ; Okada, Motohiro ; Yoshida, Shukuko ; Ueno, Shinya ; Mori, Fumiaki ; Takahara, Tomoko ; Saito, Ryo ; Miura, Yoshiki ; Kishi, Akihiro ; Tomiyama, Masahiko ; Sato, Akira ; Kojima, Toshio ; Fukuma, Goryu ; Wakabayashi, Koichi ; Hase, Kouji ; Ohno, Hiroshi ; Kijima, Hiroshi ; Takano, Yukio ; Mitsudome, Akihisa ; Kaneko, Sunao ; Hirose, Shinichi. / Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype. In: Journal of Neuroscience. 2008 ; Vol. 28, No. 47. pp. 12465-12476.
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T1 - Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype

AU - Zhu, Gang

AU - Okada, Motohiro

AU - Yoshida, Shukuko

AU - Ueno, Shinya

AU - Mori, Fumiaki

AU - Takahara, Tomoko

AU - Saito, Ryo

AU - Miura, Yoshiki

AU - Kishi, Akihiro

AU - Tomiyama, Masahiko

AU - Sato, Akira

AU - Kojima, Toshio

AU - Fukuma, Goryu

AU - Wakabayashi, Koichi

AU - Hase, Kouji

AU - Ohno, Hiroshi

AU - Kijima, Hiroshi

AU - Takano, Yukio

AU - Mitsudome, Akihisa

AU - Kaneko, Sunao

AU - Hirose, Shinichi

PY - 2008/11/19

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N2 - Mutations of genes encoding α4, β2, or α2 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.

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