Department of Biological Sciences, Vanderbilt University, Nashville, TN 37203, USA.
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37203, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37203, USA; Department of Pharmacology, Vanderbilt University, Nashville, TN 37203, USA; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37203, USA.
Curr Biol. 2017 Aug 7;27(15):2318-2330.e3. doi: 10.1016/j.cub.2017.06.046. Epub 2017 Jul 27.
Activity-dependent synaptic remodeling occurs during early-use critical periods, when naive juveniles experience sensory input. Fragile X mental retardation protein (FMRP) sculpts synaptic refinement in an activity sensor mechanism based on sensory cues, with FMRP loss causing the most common heritable autism spectrum disorder (ASD), fragile X syndrome (FXS). In the well-mapped Drosophila olfactory circuitry, projection neurons (PNs) relay peripheral sensory information to the central brain mushroom body (MB) learning/memory center. FMRP-null PNs reduce synaptic branching and enlarge boutons, with ultrastructural and synaptic reconstitution MB connectivity defects. Critical period activity modulation via odorant stimuli, optogenetics, and transgenic tetanus toxin neurotransmission block show that elevated PN activity phenocopies FMRP-null defects, whereas PN silencing causes opposing changes. FMRP-null PNs lose activity-dependent synaptic modulation, with impairments restricted to the critical period. We conclude that FMRP is absolutely required for experience-dependent changes in synaptic connectivity during the developmental critical period of neural circuit optimization for sensory input.
活动依赖性突触重构发生在早期使用的关键时期，此时幼稚的青少年会经历感官输入。脆性 X 智力迟钝蛋白 (FMRP) 通过基于感官线索的活动传感器机制来塑造突触细化，FMRP 的缺失会导致最常见的遗传性自闭症谱系障碍 (ASD)，脆性 X 综合征 (FXS)。在映射良好的果蝇嗅觉回路中，投射神经元 (PN) 将外周感觉信息传递到中央大脑蘑菇体 (MB) 学习/记忆中心。FMRP 缺失的 PN 减少了突触分支并扩大了末梢，具有超微结构和突触重建 MB 连接缺陷。通过气味刺激、光遗传学和转基因破伤风毒素神经传递阻断的关键期活动调节表明，升高的 PN 活性可模拟 FMRP 缺失缺陷，而 PN 沉默则导致相反的变化。FMRP 缺失的 PN 失去了活动依赖性突触调节，这种损伤仅限于关键期。我们得出的结论是，FMRP 绝对需要在感觉输入的神经回路优化的发育关键期内进行经验依赖性的突触连接变化。
