Structural and functional consequences of a human nicotinic receptor mutation

常染色体显性夜间额叶癫痫（autosomal dominant nightmale frontal lobe epilepsy，ADNFLE）是人类遗传性癫痫的一种特殊类型，其缺陷基因的发现为研究人类遗传性癫痫的基本机制提供了第一个机会。在这项研究项目中，定量方法成像的大脑将被用来桥梁差距之间的理解，这是分子缺陷和临床表现的ADNFLE。假设涉及神经通路系统，皮质中多巴胺能系统，以解释在ADNFLE癫痫发作的额叶的优先易感性。正电子发射断层扫描将用于检查额叶神经递质释放的变化。ADNFLE中的分子缺陷也提供了一个独特的机会来研究烟碱受体在人类大脑发育和人类认知的重要方面中的作用。将使用解剖变异性的统计映射和高分辨率磁共振扫描来检测内侧额叶解剖结构的改变。将使用一系列对尼古丁效应敏感的心理测试来寻找ADNFLE中尼古丁受体介导的认知效应缺陷的证据。

Identification of the defective gene underlying a particular form of inherited epilepsy in man, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), now provides the first opportunity to study the basic mechanisms of an inherited epilepsy in man. The responsible mutations affect a subunit of the nicotinic acetylcholine receptor. In this research project, quantitative methods of imaging the brain will be used bridge the gap in understanding which lies between the molecular defect and the clinical manifestations of ADNFLE. Involvement of a system of nerve pathways, the mesocortical dopaminergic system, is postulated to explain the preferential susceptibility of the frontal lobe to seizures in ADNFLE. Positron emission tomography will be used to examine changes in neurotransmitter release in the frontal lobe. The molecular defect in ADNFLE also provides a unique opportunity to examine the role of the nicotinic receptor in the development of the human brain and in important aspects of human cognition. Statistical mapping of anatomical variability and high resolution magnetic resonance scans will be used to detect alterations in the anatomical structure of the mesial frontal lobe. Evidence of deficient nicotinic receptor-mediated cognitive effects in ADNFLE will be sought using a battery of psychological tests shown to be sensitive to the effects of nicotine.