2010 Fiscal Year Final Research Report
Establishment of preventive strategies for nocturnal frontal lobe epilepsy-Elucidation of molecular mechanism to inhibit epileptic seizures
| Project/Area Number |
20591361
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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 |
Psychiatric science
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| Research Institution | Hirosaki University |
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Principal Investigator |
MORI Fumiaki Hirosaki University, 大学院・医学研究科, 准教授 (60200383)
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| Co-Investigator(Kenkyū-buntansha) |
MIGITA Keisuke 弘前大学, 大学院・医学研究科, 助教 (10352262)
UENO Shinya 弘前大学, 大学院・医学研究科, 教授 (00312158)
WAKABAYASHI Koichi 弘前大学, 大学院・医学研究科, 教授 (50240768)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 内科系臨床医学 / 精神神経科学 |
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| Research Abstract |
Mutations of genes encoding α4, ss2 or α2 subunits (CHRNA4, CHRNB2 or CHRNA2, respectively), of neuronal nicotinic acetylcholine (ACh) receptor (nAChR) cause nocturnal frontal lobe epilepsy (NFLE) in human. NFLE-related seizures are seen exclusively during sleep and 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 central nervous system, 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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[Journal Article] Rats harboring S284L Chrna4 mutation show attenuation of synaptic and extrasynaptic GABAergic transmission and exhibit the nocturnal frontal lobe epilepsy phenotype.2008
Author(s)
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
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Journal Title
J Neurosci 28
Pages: 12465-12476
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