| Project/Area Number |
15300146
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | Fukuoka University |
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Principal Investigator |
MITSUDOME Akihisa Fukuoka University, School of Medicine, Professor, 医学部, 教授 (30038749)
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| Co-Investigator(Kenkyū-buntansha) |
HIROSE Shinichi Fukuoka University, School of Medicine, Assistant professor, 医学部, 助教授 (60248515)
DESHIMARU Masanobu Fukuoka University, Department of Science, Assistant, 理学部, 助手 (70309889)
ARAKI Kimi Kumamoto University, Institute of Molecular Embryology and Genetics, Assistant professor, 発生医学研究センター, 助教授 (90211705)
KANEKO Sunao Hirosaki University, School of Medicine, Professor, 医学部, 教授 (40106852)
OKADA Motohiro Hirosaki University, School of Medicine, Lecturer, 医学部, 講師 (10281916)
鈴木 登志郎 日本エスエルシー(株), 受託試験部, 課長
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥16,600,000 (Direct Cost: ¥16,600,000)
Fiscal Year 2005: ¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 2004: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2003: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Keywords | Model Animal / Transgenic Animal / Epilepsy / Channel / Channelopahty / Transgenome / Sleep / Neurotransmitter / ラット / 遺伝子 |
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| Research Abstract |
Mutations of nicotinic-acetylcholine receptor (nAChR) have been identified in both autosomal dominant (ADNFLE) and sporadic (NFLE) nocturnal frontal-lobe epilepsies. To explore the pathomechanism of ADNFLE/NFLE, we generated transgenic-rats named "S284L-TG"harboring S284L mutant CHRNA4 (identified in human ADNFLE/NFLE). Screening tests (fertility, longevity, physical development, histopathology, behaviors and distorted Chrna4 mRNA expression) revealed no obvious abnormalities in S284L-TG. S284L-TG showed three types of spontaneous epileptic-seizures (paroxysmal-arousals, paroxysmal-dystonia and epileptic-wandering), generated in sensorimotor-cortex during sleep, resembling those of ADNFLE/NFLE patients, and responded to antiepileptic drugs used in ADNFLE/NFLE. We here report unique dysfunctions of α4(S284L)β2-nAChR that plays important roles in pathomechanisms of ADNFLE/NFLE. In the epileptic-focus(sensorimotor-cortical layers II/III and V pyramidal neurons), α4(S284L)β2-nAChR preferentially attenuated both GABAergic synaptic- and tonic-inhibitions, while retained the glutamatergic counterpart. This disinhibition induced by such a dissociated-dysfunction ofα4(S284L)β2-nAChR enhanced both glutamatergic transmission from sensorimotor-cortical layers II/III to V and frontal glutamate release without changing GABA. The latter phenomenon was accelerated by sleep. This imbalance of sensorimotor-cortical transmission of S284L-TG was accelerated by depletion of Ca^<2+> in synaptic clefts. Our study indicates the unique dysfunction of α4(S284L)β2-nAChR (attenuation of Ca^<2+>-sensitivity, GABAergic synaptic- and tonic-inhibitions) contributes to the pathomechanisms of ADNFLE/NFLE and S284L/TG seems a suitable model of ADNFLE/NFLE.
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