MULTIPLE ROLES OF FMRP IN SYNAPTIC FUNCTION AND PLASTICITY

描述（由申请人提供）：由于Fmr 1基因突变导致脆性X智力低下蛋白（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在突触中的功能进行了二十年的深入研究，但对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起作用，并且迄今为止对FXS的研究集中在FMRP损失导致改变的长期突触可塑性（LTP）的突触后效应上。虽然LTP被认为在学习和记忆中发挥重要作用，但人们普遍认为短期可塑性（STP）控制其他基本神经功能，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。然而，FXS中的STP失调很少受到关注，并且了解甚少。此外，FMRP是否在控制STP的突触机制中发挥作用仍然是未知的。我们最近的研究表明，FMRP的缺失导致了兴奋性海马突触的STP缺陷和异常的信息处理。我们进一步证明，FMRP的损失导致异常增加的一个主要的钙依赖性形式的快速突触前增强，称为增强，和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的改变是FMRP缺失时STP缺陷的主要潜在原因。重要的是，我们的研究结果表明，至少有一些这些缺陷的潜在机制有一个细胞自主的突触前起源，并从一个新的FMRP功能，这是不相关的蛋白质翻译的传统作用。我们建议将联合收割机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;（iii）确定与FMRP丢失相关的突触异常对典型神经回路执行的计算的影响。我们预期这些研究将为FMRP在突触中的功能提供基本的新见解，并为FXS中的突触功能障碍提供新的方法。

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.