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: 8876830
• 负责人: Vitaly A Klyachko
• 金额: $ 33.55万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876830
• 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; presynaptic neurons; 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.

描述（由申请人提供）：由于 Fmr1 基因突变导致脆性 X 型智力迟钝蛋白 (FMRP) 缺失，导致脆性 X 综合征 (FXS)，这是遗传性精神残疾的最常见形式，也是自闭症的主要遗传原因。尽管对 FMRP 在突触功能的特征进行了二十年的深入研究，但 FXS 的分子基础仍然知之甚少。 FMRP 被认为主要作为树突中蛋白质合成的调节剂，迄今为止 FXS 的研究主要集中在 FMRP 损失导致长期突触可塑性 (LTP) 改变的突触后效应上。虽然 LTP 被认为在学习和记忆中发挥着重要作用，但人们普遍认为短期可塑性 (STP) 控制着其他重要的神经功能，例如信息处理、工作记忆和决策。因此，STP 失调可能在 FXS 认知障碍中发挥重要作用。然而，FXS 中的 STP 失调很少受到关注，而且了解甚少。此外，FMRP 是否在控制 STP 的突触机制中发挥作用仍然很大程度上未知。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 缺陷和信息处理异常。我们进一步证明，FMRP 损失会导致主要的钙依赖性快速突触前增强（称为增强）异常增加，并且突触前神经元中的钙流入也会增加。因此，我们假设突触前钙动力学的改变是在没有 FMRP 的情况下 STP 缺陷的一个主要原因。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，并且源于一种新的 FMRP 功能，该功能与其在蛋白质翻译中的传统作用无关。我们建议将电生理学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 的损失如何改变钙动力学和 STP； (ii) 检查 FMRP 调解这些缺陷的功能； (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。我们预计这些研究将为 FMRP 在突触中的功能提供基本的新见解，并为解决 FXS 中的突触功能障碍提供一种新方法。