Experience-dependent regulation of the Fragile X gene

描述（由申请人提供）：神经科学的一个基本问题是理解短暂的经验如何转化为突触结构和功效的稳定变化。这种持久的突触修饰的产生需要新的蛋白质合成，而新的蛋白质合成又在转录和翻译水平上受到调节。此外，神经元的转录谱是其发育阶段（例如关键期）及其激活历史的函数。解开长期可塑性机制的一个主要挑战是将发育时间和经验诱导的神经活动与在突触可塑性中起关键作用的已鉴定分子的调节联系起来。脆性X综合征（FXS）为这个问题的核心提供了一个门户。FXS影响约1：4000的男孩，由三重重复扩增和Fmr 1启动子的超甲基化引起，导致基因沉默。Fmr 1基因的蛋白产物FMRP在调节蛋白质合成依赖性突触可塑性中起着重要作用。本实验室已建立了体内和细胞培养系统，用于研究Fmr 1的转录和表达。我们发现，Fmr 1的成绩单是非常丰富的发展和成人嗅球和双向调节的嗅觉经验。初步体内和CE|培养物研究提供了两种调节Fmr 1转录的分子机制的证据：转录因子AP-2a和选择性的、发育调节的Fmr 1基因调控区的表观遗传修饰。在拟议的研究中，我们将使用嗅觉系统与遗传和细胞培养模型，以阐明在完整的中枢神经系统中的Fmr 1基因调控的分子逻辑。

DESCRIPTION (provided by applicant): A fundamental problem in neuroscience is understanding how ephemeral episodes of experience are transformed into stable changes in synaptic architecture and efficacy. The creation of such long-lasting synaptic modifications requires new protein synthesis, which in turn is regulated at both transcriptional and translational levels. Moreover, the transcriptional profile of the neuron is a function of its developmental stage - e.g. critical period - and its history of activation. A major challenge in unraveling the mechanisms of long term plasticity then is to relate both developmental timing and experience-induced neural activity to the regulation of identified molecules that play key roles in synaptic plasticity. Fragile X Syndrome (FXS) offers a portal to the heart of this problem. FXS affects about 1:4000 boys and is caused by a triplet repeat expansion and hypermethylation of the Fmr1 promoter, leading to gene silencing. The protein product of the Fmr1 gene, FMRP, plays a central role in regulating protein synthesis-dependent synaptic plasticity. Our laboratory has established in vivo and cell culture systems for the study of Fmr1 transcription and expression. We find that Fmr1 transcripts are highly abundant in the developing and adult olfactory bulb and are bi-directionally regulated by olfactory experience. Preliminary in vivo and ce|l culture studies have provided evidence for two molecular mechanisms that regulate Fmr1 transcription: the transcription factor AP-2a and the selective, developmentally-regulated epigenetic modification of the Fmr1 gene regulatory regions. In the proposed studies we will use the olfactory system together with genetic and cell culture models to elucidate the molecular logic of Fmr1 gene regulation in the intact CNS.