| Project/Area Number |
17590856
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | Hirosaki University |
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Principal Investigator |
HAYAKARI Makoto (2006) Hirosaki University, School of Medicine and Hospital, Professor, 医学部附属病院, 助教授 (80156421)
森 文秋 (2005) 弘前大学, 医学部, 助教授 (60200383)
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| Co-Investigator(Kenkyū-buntansha) |
OKADA Motohiro Hirosaki University, School of Medicine and Hospital, Lecturer, 医学部附属病院, 講師 (10281916)
UENO Shinya Hirosaki University, School of Medicine, Professor, 医学部, 教授 (00312158)
WAKABAYASHI Koichi Hirosaki University, School of Medicine, Professor, 医学部, 教授 (50240768)
ZHU Gong Hirosaki University, School of Medicine, Assistant Professor, 医学部, 助手 (80400133)
早狩 誠 弘前大学, 医学部, 助教授 (80156421)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | autosomal dominant nocturnal frontal-lobe epilepsies / transgenic rat / nicotinic acetylcholine receptor (nAChR) / sleep / S284L α4β2-nAChR / sensorimotor cortex / 感覚運動皮質 / ニコチン性アセチルコリン受容体 / 284L α4β2-nAChR / S284L α4β2-nAChR |
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| Research Abstract |
Epilepsy is a common neurological disorder, afflicting about 1% of the general population. Autosomal dominant (ADNFLE) and sporadic (NFLE) nocturnal frontal-lobe epilepsies show a characteristic and uniform phenotype. The typical symptoms are motor-partial seizures during sleep, which appear to originate mainly in the frontal lobe. Recently, the genetic abnormalities underlying ADNFLE have been identified in CHRNA4 and CHRNB2,which encode the respective α4- and β2-subunits of nicotinic acetylcholine receptor (nAChRs). However, pathomechanisms in region-specific epileptogenesis of ADNFLE is uncertain. To elucidate the pathophysiology of ADNFLE/NFLE in relation to nAChR dysfunction, 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 distorting Chrna4 expression) revealed no obvious abnormalities in S284L-TG. S284L-TG showed three types of s
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pontaneous epileptic-seizures (paroxysmal-arousals, paroxysmal-dystonia and epileptic-wandering), generated in sensorimotor-cortex during sleep, resembling ADNFLE/NFLE patients, which responded to antiepileptic-drugs used in ADNFLE/NFLE. We here show 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 of α4(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 transmission in sensorimotor cortex 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. Less
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