Genetic Control of Synaptic Structure in the Adult Brain.

描述(申请人提供)：长期目标是确定在体内调节成人中枢突触结构可塑性的新机制。成年果蝇脑内的突触呈动态变化。此外，无论是在发育过程中还是发育后，过度激活的神经元或过度表达活性的Raf，似乎都会诱导异位突触。成年中枢突触结构动力学将使用长期多光子共聚焦成像在整个活体苍蝇的大脑中进行研究。对神经活动的依赖性将在基因过度激活或使发育后成像的神经元沉默的同时进行检查。调节成人中枢突触结构的分子机制将通过过度表达候选基因来探索，例如那些在丝裂原激活激酶途径中的候选基因，如果时间允许，还将随机筛选成人大脑中过度表达的基因，选择那些显示出突触前和突触后标记异常模式的苍蝇系。已确定的基因将被克隆，其功能丧失的表型将使用RNAi进行表征。了解和利用这些分子机制将有助于预防和治疗精神障碍，精神障碍往往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.