Genetic Control of Synaptic Structure in the Adult Brain.

描述（由申请人提供）：长期目标是确定体内调节成人中枢突触结构可塑性的新机制。突触在成年果蝇大脑中表现为动态的。此外，过度激活的神经元，或过度表达一个活跃的Raf，无论是在整个或发育后，似乎诱导异位突触。本文将利用长时多光子共聚焦成像技术研究活蝇全脑的成虫中枢突触结构动力学。对神经活动的依赖将在基因过度激活或发育后成像神经元沉默时进行检查。通过过度表达候选基因（如丝裂原活化激酶途径中的候选基因），以及在时间允许的情况下，在成人大脑中随机筛选过度表达基因的果蝇系，选择那些显示异常模式的荧光突触前和突触后标记物，来探索调节成人中枢突触结构的分子机制。鉴定出的基因将被克隆，它们的功能缺失表型将使用RNAi进行表征。理解和利用这些分子机制将有助于预防和治疗精神障碍，这通常与突触结构的破坏有关。

DESCRIPTION (provided by applicant): The long-term objective is to identify novel mechanisms regulating adult central synaptic structural plasticity in vivo. Synapses appear dynamic in adult Drosophila brain. In addition, hyper-activating neurons, or over-expressing an active Raf, either throughout or after development, seems to induce ectopic synapses. Adult central synaptic structural dynamics will be investigated using long-term multi-photon confocal imaging in the brains of live whole flies. Dependence on neural activity will be examined while genetically hyper-activating or silencing the imaged neurons post-developmentally. Molecular mechanisms regulating adult central synaptic structure will be explored by over-expressing candidate genes, such as those in the mitogen-activated kinase pathway, and, if time permits, screening fly lines randomly over-expressing genes in adult brains, selecting those showing abnormal patterns of fluorescent pre- and post-synaptic markers. Identified genes will be cloned and their loss-of-function phenotypes will be characterized using RNAi. Understanding and harnessing these molecular mechanisms will contribute to the prevention and treatment of mental disorders, which are often associated with the disruption of synaptic structure.