Modeling Fragile X Syndrome in Drosophilia

描述（由申请人提供）：脆性X综合征是最常见的遗传性智力低下之一，由FMR1基因功能丧失引起。脆性X综合征患者会出现多种症状，包括；智力迟钝、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。在之前的研究中，我们已经基于dfmr1功能突变缺失的果蝇脆性X模型进行了表征。令人惊讶的是，dfmr1突变体显示出几种与脆性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调节和神经解剖缺陷。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综合征症状的原因之一。为了支持这一模型，我们之前证明了使用mGluR拮抗剂治疗可以挽救几种dfmr1突变型，包括求爱缺陷、记忆和一些神经解剖缺陷。我们现在准备检查cAMP调节缺陷的生物学相关性。我们还将绘制大脑中dfmr1对正常昼夜节律行为的要求。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节律行为的机制。这些研究将影响我们对导致脆性X染色体的主要缺陷的基本理解，并提高我们对认知过程和昼夜节律行为的一般认识。公共卫生相关性：本提案从多个层面研究果蝇脆性X综合征模型，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。这项研究的发现将增加我们对导致脆性X的潜在缺陷的理解，并增加我们对正确认知和昼夜节律行为要求的基本知识，以及小RNA途径如何与FMR1联系。

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.