Generation of epilepsy model animal bearing a genetic abnormality identified in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) of human

产生人类常染色体显性遗传性夜间额叶癫痫（ADNFLE）遗传异常的癫痫模型动物

• 批准号: 18390316
• 负责人: OKADA Motohiro
• 金额: $ 11.88万
• 依托单位: Mie University (2007-2009)Hirosaki University (2006)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390316/
• 关键词: てんかん; 病態; トランスジェニックラット; 遺伝子; 分子生物学; 神経伝逹; 神経伝達; 認知機能

Mutations of genes encoding α4, 2 or α2 subunits (CHRNA4, CHRNB2, or CHRNA2, respectively) of neuronal nicotinic ACh receptor nAChR) 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 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 rats exhibited two major abnormalities in neurotransmission : (1) enhanced AMPA/glutamatergic excitatory transmission in focus region 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.

人类神经元烟碱乙酰胆碱受体(nAChR) α4、α2或α2亚基（分别为CHRNA4、CHRNB2和CHRNA2）编码基因突变可引起夜间额叶癫痫（NFLE）。nfl相关的癫痫发作只在睡眠中出现，并以三种不同的癫痫发作表型为特征：“阵发性觉醒”、“阵发性肌张力障碍”和“发作性徘徊”。我们产生了含有错义突变S284L的转基因大鼠菌株，该突变已在NFLE的CHRNA4中被鉴定出来。转基因大鼠没有生物学异常，如中枢神经系统畸形和行为异常。转基因大鼠在慢波睡眠（SWS）中表现出与NFLE相似的癫痫发作表型，表现出三种特征性发作表型，从而符合人类NFLE的诊断标准。大鼠在神经传递方面表现出两大异常：(1)焦区AMPA/谷氨酸兴奋性传递增强；(2)SWS时谷氨酸释放异常。目前可用的癫痫基因工程动物模型仅限于小鼠；因此，我们的转基因大鼠为癫痫研究领域提供了另一个维度。

项目成果

Frontal dysfunction during a cognitive task in drug-naive patients with panic disorder as investigated by multi-channel near-infared spectroscopy imaging.

通过多通道近红外光谱成像研究未接受药物治疗的惊恐障碍患者在认知任务期间的额叶功能障碍。

• 发表时间: 2007
• 期刊: Neurosci Res. 59
• 作者: Nishimura Y;Tanii H;Fukuda M;Kajiki N;Inoue K;Kaiya H;Nishida A;Okada M;Okazaki Y.
• 通讯作者: Okazaki Y.

Regulation of Dictyostelium prestalk-specific gene expression by a SHAQKY family MYB transcription factor. Development.

SHAQKY 家族 MYB 转录因子对盘基网柄菌前柄特异性基因表达的调节。

• 发表时间: 2006
• 期刊: Development 133
• 作者: Fukuzawa;M.;et al.
• 通讯作者: et al.

プロテインキナーゼCに対するトピラマートの効果の検討.

检查托吡酯对蛋白激酶 C 的影响。

• 发表时间: 2009
• 作者: 吉田淑子;岡田元宏;吉田秀一;兼子直
• 通讯作者: 兼子直

けいれん性疾患に関連する遺伝子変異とけいれん性疾患診断方法

惊厥性疾病相关基因突变及惊厥性疾病诊断方法

• 发表时间: 2006

Rats Harboring S284L Chrna4 Mutation Show Attenuation of Synaptic and Extrasynaptic GABAergic Transmission and Exhibit the Nocturnal Frontal Lobe Epilepsy Phenotype.

携带 S284L Chrna4 突变的大鼠显示突触和突触外 GABA 能传递减弱，并表现出夜间额叶癫痫表型。

• 发表时间: 2008
• 期刊: J Neurosci 28(47)
• 作者: Hirose S.;et al
• 通讯作者: et al