MULTIPLE ROLES OF FMRP IN SYNAPTIC FUNCTION AND PLASTICITY

FMRP 在突触功能和可塑性中的多种作用

• 批准号: 8343696
• 负责人: Vitaly A Klyachko
• 金额: $ 34.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8343696
• 关键词: Action Potentials; Acute; Affect; Attention; Autistic Disorder; Back; Biological; Brain; Calcium; Cells; Chemosensitization; Decision Making; Defect; Dendrites; Due Process; Electrophysiology (science); Excitatory Synapse; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional disorder; Genes; Genetic; Goals; Hippocampus (Brain); Image; Impaired cognition; Individual; Inherited; Inhibitory Synapse; Interneurons; Learning; Mediating; Memory; Mental Retardation; Molecular; Mus; Mutation; Neurons; Neurophysiology - biologic function; Output; Pharmacology; Play; Presynaptic Terminals; Process; Property; Protein Biosynthesis; Proteins; Psyche structure; Pyramidal Cells; Research; Role; Shapes; Short-Term Memory; Slice; Synapses; Synaptic plasticity; Testing; Translations; Viral; Work; base; disability; excitatory neuron; feeding; in vivo; information processing; insight; neural circuit; novel; operation; postsynaptic; presynaptic; protein expression; protein function; research study; synaptic function; tool; two-photon

DESCRIPTION (provided by applicant): Loss of Fragile X mental retardation protein (FMRP) due to mutations in the Fmr1 gene causes Fragile X syndrome (FXS), the most common form of inherited mental disability and the leading genetic cause of autism. Despite two decades of intensive studies characterizing FMRP functions at synapses, the molecular basis of FXS remains poorly understood. FMRP is thought to function primarily as a regulator of protein synthesis in dendrites, and research to date on FXS has concentrated on the postsynaptic effects of FMRP loss leading to altered long-term synaptic plasticity (LTP). While LTP is thought to play important roles in learning and memory, short-term plasticity (STP) is widely believed to control other essential neural functions such as information processing, working memory and decision making. STP dysregulation may thus play a significant role in the cognitive impairments in FXS. However, STP dysregulation in FXS has received little attention and is poorly understood. Moreover, whether FMRP plays a role in synaptic mechanisms controlling STP remains largely unknown. Our recent studies revealed that loss of FMRP causes marked STP defects and abnormal information processing in excitatory hippocampal synapses. We further demonstrated that FMRP loss causes abnormal increase of a major calcium-dependent form of rapid presynaptic enhancement, known as augmentation, and that the calcium influx in presynaptic neurons is also increased. We therefore hypothesize that altered presynaptic calcium dynamics represents a major underlying cause of STP defects in the absence of FMRP. Importantly, our results indicate that at least some of the underlying mechanisms of these defects have a cell-autonomous presynaptic origin and arise from a novel FMRP function that is not related to its traditional role in protein translation. We propose to combine electrophysiological and imaging approaches with pharmacology and molecular biological tools to (i) determine how loss of FMRP alters calcium dynamics and STP; (ii) Examine the functions of FMRP mediating these defects; and (iii) Determine the impact of synaptic abnormalities associated with FMRP loss on computations performed by canonical neural circuits. We anticipate that these studies will provide fundamental new insights into the function of FMRP in synapses and a novel way to approach synaptic dysfunction in FXS. PUBLIC HEALTH RELEVANCE: Fragile X syndrome, which is attributed to loss of Fragile X mental retardation protein (FMRP), represents the most common inherited form of mental retardation and the leading genetic cause of autism, yet the mechanisms underlying the cognitive impairments in Fragile X syndrome remain poorly understood. We propose to investigate novel functions of FMRP leading to dysregulation in short-term plasticity, which is widely believed to play important roles in the brain's ability to analyze information. Our studies will provide fundamental new insights into the function of FMRP in synapses and will help elucidate the molecular mechanisms of FXS.

描述(由申请人提供)：由于Fmr1基因突变导致的脆性X智力低下蛋白(FMRP)的丢失会导致脆性X综合征(FXS)，这是遗传性智力残疾的最常见形式，也是自闭症的主要遗传原因。尽管二十年来对FMRP在突触上的功能进行了深入的研究，但FXS的分子基础仍然知之甚少。FMRP被认为主要作为树突蛋白质合成的调节因子，到目前为止，对FXS的研究主要集中在FMRP丢失导致突触长期可塑性(LTP)改变的突触后效应上。虽然LTP被认为在学习和记忆中起着重要的作用，但人们普遍认为短期可塑性(STP)控制着其他基本的神经功能，如信息处理、工作记忆和决策。因此，STP调节失调可能在FXS的认知损害中起重要作用。然而，FXS中的STP调控失调却鲜有人关注，也知之甚少。此外，FMRP是否在控制STP的突触机制中发挥作用在很大程度上仍不清楚。我们最近的研究表明，FMRP的缺失会导致兴奋性海马突触中明显的STP缺陷和异常的信息处理。我们进一步证明，FMRP的丢失导致一种主要的钙依赖的突触前快速增强形式异常增加，即突触前增强，突触前神经元的钙内流也增加。因此，我们假设突触前钙动力学改变是在没有FMRP的情况下STP缺陷的主要潜在原因。重要的是，我们的结果表明，这些缺陷的至少一些潜在机制具有细胞自主的突触前起源，并源于一种与其在蛋白质翻译中的传统角色无关的新的FMRP功能。我们建议将电生理和成像方法与药理学和分子生物学工具相结合，以(I)确定FMRP丢失如何改变钙动力学和STP；(Ii)检查FMRP介导这些缺陷的功能；以及(Iii)确定与FMRP丢失相关的突触异常对规范神经回路执行的计算的影响。我们期待这些研究将为FMRP在突触中的功能提供新的基本见解，并为探讨FXS中的突触功能障碍提供一种新的方法。 与公共卫生相关：脆性X综合征，可归因于脆性X智力低下蛋白(FMRP)的丢失，是最常见的遗传性智力低下形式，也是导致自闭症的主要遗传原因，但脆性X综合征认知障碍的潜在机制仍知之甚少。我们建议研究FMRP在短期可塑性中导致失调的新功能，人们普遍认为FMRP在大脑分析信息的能力中发挥着重要作用。我们的研究将为FMRP在突触中的功能提供新的基础，并有助于阐明FXS的分子机制。