MULTIPLE ROLES OF FMRP IN SYNAPTIC FUNCTION AND PLASTICITY

描述（由申请人提供）：由于Fmr1基因突变导致脆性X智力迟钝蛋白（FMRP）的缺失导致脆性X综合征（FXS），这是最常见的遗传性精神残疾形式，也是自闭症的主要遗传原因。尽管二十年来对FMRP在突触中的功能进行了深入研究，但FXS的分子基础仍然知之甚少。FMRP被认为主要作为树突蛋白质合成的调节因子，迄今为止关于FXS的研究主要集中在FMRP缺失导致长期突触可塑性（LTP）改变的突触后效应。LTP被认为在学习和记忆中发挥重要作用，短期可塑性（STP）被广泛认为控制着其他重要的神经功能，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，STP在FXS中的失调很少受到关注，也很少被理解。此外，FMRP是否在控制STP的突触机制中起作用仍不清楚。我们最近的研究表明，FMRP的缺失导致了显著的STP缺陷和海马兴奋性突触的异常信息处理。我们进一步证明，FMRP缺失导致一种主要的钙依赖形式的快速突触前增强（称为增强）异常增加，并且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在缺乏FMRP的情况下STP缺陷的主要潜在原因。重要的是，我们的研究结果表明，至少这些缺陷的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，而这种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结合起来：(i)确定FMRP的丢失如何改变钙动力学和STP；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典型神经回路执行计算的影响。我们预计这些研究将为FMRP在突触中的功能提供新的基础见解，并为FXS的突触功能障碍提供新的途径。

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.