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

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。

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.