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, Koji Hase, Hiroshi Ohno, Hiroshi Kijima, Yukio Takano, Akihisa Mitsudome, Sunao KanekoShinichi Hirose

Research output: Contribution to journalArticlepeer-review

46 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

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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