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基因突变引起的脆弱X智力低下蛋白（FMRP）的丧失导致脆弱的X综合征（FXS），X综合征（FXS）是遗传性精神残疾和自闭症的主要遗传原因的最常见形式。尽管在突触中表征了FMRP功能的二十年进行了深入的研究，但FXS的分子基础仍然很少了解。 FMRP被认为主要是树突中蛋白质合成的调节剂，迄今为止，FXS的研究集中在FMRP损失的突触后作用上，导致长期突触可塑性（LTP）改变。虽然LTP被认为在学习和记忆中起着重要作用，但短期可塑性（STP）被广泛认为可以控制其他基本神经功能，例如信息处理，工作记忆和决策。因此，STP失调可能在FXS的认知障碍中起重要作用。但是，FXS中的STP失调几乎没有引起关注，并且知之甚少。此外，FMRP是否在控制STP的突触机制中发挥作用，在很大程度上未知。我们最近的研究表明，FMRP的丧失导致兴奋性海马突触中明显的STP缺陷和异常信息处理。我们进一步证明，FMRP损失会导致主要钙依赖性形式的快速突触前增强（称为增强）的异常增加，并且突触前神经元的钙涌入也增加。因此，我们假设改变的突触前钙动力学代表了在没有FMRP的情况下STP缺陷的主要根本原因。重要的是，我们的结果表明，这些缺陷的至少某些潜在机制具有细胞自主的突触前起源，并且源于新型的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，以确定FMRP的损失如何改变钙动力学和STP； （ii）检查介导这些缺陷的FMRP的功能； （iii）确定与FMRP损失相关的突触异常对规范神经回路进行的计算的影响。我们预计，这些研究将为FMRP在突触中的功能以及一种解决FXS突触功能障碍的新方法提供基本的新见解。