Modeling Fragile X Syndrome in Drosophilia

描述(申请人提供)：脆性X综合征是最常见的遗传性智力低下形式之一，由FMR1基因功能丧失引起。脆性X综合征患者患有各种症状，包括智力低下、注意力缺陷、多动、睡眠障碍、焦虑、情绪不稳定和自闭症样行为。在以前的研究中，我们已经描述了基于dfmr1功能突变丢失的脆性X的果蝇模型。令人惊讶的是，dfmr1突变体表现出几种与脆性X症状相似的表型。这些表型包括求爱缺陷、记忆缺陷、缺乏适当的昼夜节律和神经解剖缺陷。最近的观察表明，代谢性谷氨酸受体(MGluR)信号的增强是导致大量脆性X症状的原因。为了支持这一模型，我们先前证明了用mGluR拮抗剂治疗可以挽救dfmr1突变的几种表型，包括求偶缺陷、记忆缺陷和一些神经解剖缺陷。我们现在准备研究报告的cAMP监管缺陷的生物学相关性。我们还将绘制大脑中dfmr1对正常昼夜行为的要求。在另一项研究中，我们一直在研究dFMR1与小RNA途径的一个关键成员一起调节昼夜行为的机制。这些研究将影响我们对导致脆性X的主要缺陷的基本理解，以及提高我们对认知过程和昼夜行为的一般知识。公共卫生相关性：这项建议在多个水平上调查脆性X综合征的果蝇模型，包括检查导致记忆和昼夜行为相关表型的生理和神经元回路缺陷。这项研究的发现既将增加我们对导致脆性X的潜在缺陷的理解，也将增加我们关于正确认知和昼夜行为所需的基本知识，以及小RNA途径如何与FMR1联系起来。

DESCRIPTION (provided by applicant): Fragile X syndrome is one of the most commonly inherited forms of mental retardation and is caused by the loss of FMR1 gene function. Patients with fragile X syndrome suffer from a variety of symptoms including; mental retardation, attention deficit, hyperactivity, sleep disorders, anxiety, unstable mood and autistic-like behaviors. In previous studies, we have characterized a Drosophila model for Fragile X, based on dfmr1 loss of function mutations. Surprisingly, dfmr1 mutants display several phenotypes that bear similarity to Fragile X symptoms. These phenotypes include courtship defects, memory deficits, lack of proper circadian regulation and neuroanatomical defects. Recent observations have indicated that enhanced metabotropic glutamate receptor (mGluR) signaling is a cause of a large number of the Fragile X symptoms. In support of this model, we previously demonstrated that treatment with mGluR antagonists rescues several of the dfmr1 mutant phenotypes, including the courtship defects, memory and some neuroanatomical defects. We now are poised to examine the biological relevance of a reported deficit in cAMP regulation. We will also map the requirements of dfmr1 in the brain for normal circadian behavior. In another study we have been investigating the mechanism by which dFMR1 functions with a key member of the small RNA pathways to regulate circadian behavior. These studies will impact our basic understanding of the primary defects that lead to fragile X, as well a improve our general knowledge of the processes of cognition and circadian behavior. PUBLIC HEALTH RELEVANCE: This proposal investigates a Drosophila model for Fragile X Syndrome at multiple levels, including examination of defects in physiology and neuronal circuits that cause relevant phenotypes in memory and circadian behavior. Findings from this research will both increase our understanding of the underlying defects that cause fragile X as well as increase our basic knowledge on the requirements for proper cognition and circadian behavior, as well as how the small RNA pathway is linked to the FMR1.