Department of Cell Biology and Physiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Neurosci. 2011 Jul 27;31(30):10971-82. doi: 10.1523/JNEUROSCI.2021-11.2011.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍形式，也是自闭症的主要遗传病因。它与脆性 X 智力低下蛋白（FMRP）的缺乏有关，FMRP 是轴突和树突中蛋白质合成的调节剂。FXS 的研究主要集中在长期可塑性功能障碍的突触后变化上。相比之下，FXS 的突触前机制受到的关注相对较少，并且了解甚少。依赖活动的突触前过程产生了几种形式的短期可塑性（STP），据信它控制着一些基本的神经功能，包括信息处理、工作记忆和决策制定。然而，STP 缺陷的程度及其对 FXS 病理生理学的贡献在很大程度上仍然未知。在这里，我们报道了 Fmr1 敲除（KO）小鼠兴奋性海马突触的明显突触前异常，导致 STP 和信息处理缺陷。FMRP 的缺失导致对高频刺激的反应增强。Fmr1 KO 小鼠还表现出自然刺激序列的异常突触处理，特别是与海马位置场相关的高频尖峰放电期间的过度增强。对单个 STP 成分的分析显示，由于 FMRP 的缺失，增强和短期压抑的作用明显增强。这些变化与高频刺激期间突触前神经元中钙内流的增加、突触小泡的再循环增强以及可释放和保留的小泡池增大有关。这些数据表明，FMRP 的缺失导致异常的 STP 和信息处理，这可能是 FXS 认知障碍的一个新机制。
