Temporal requirements of the fragile X mental retardation protein in modulating circadian clock circuit synaptic architecture
Temporal requirements of the fragile X mental retardation protein in modulating circadian clock circuit synaptic architecture
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DOI：
10.3389/neuro.04.008.2009
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发表时间：
2009-08-01
影响因子：
3.5
通讯作者：
Broadie, Kendal
中科院分区：
文献类型：
--
作者：
Gatto, Cheryl L.;Broadie, Kendal
脆性X智力发育迟滞1 （FMR1）基因功能缺失是遗传性智力发育迟滞和自闭症谱系障碍的最常见原因，其特征是注意力障碍、多动和昼夜活动周期中断。寻求有效的干预策略需要确定何时需要FMR1产物（FMRP）来调节控制这些行为的神经元回路。在具有良好特征的果蝇疾病模型中，高度保守的dFMRP的缺失导致昼夜节律性心律失常和昼夜节律时钟电路中的明显异常。在这里，一种新颖的Sholl分析被用于量化dfmr1-null小腹侧神经元（sLN(v)s）中过度复杂的突触结构，这是时钟神经元的一个关键子集。利用转基因基因开关系统在dfmr1-null突变背景下驱动条件神经元dFMRP表达，以剖析时钟电路中的时间要求。在早期大脑发育阶段，包括神经发生、神经元命运规范和早期寻路阶段引入dFMRP，对dfmr1突变表型没有任何拯救作用。同样，在成人中恢复正常的dFMRP表达并不能恢复昼夜节律回路结构。与之形成鲜明对比的是，在大脑发育非常晚的一个短暂窗口期提供dFMRP，在此期间突触发生和随后的大量突触重组（如使用依赖性修剪）发生，为重建正常的sLN(v)s突触树桩提供了强有力的形态学拯救。我们得出结论，dFMRP在这些神经元突触结构的塑造中起着发育限制的作用，这种作用不能通过在成熟时重新引入该蛋白来补偿。
Loss of fragile X mental retardation 1 (FMR1) gene function is the most common cause of inherited mental retardation and autism spectrum disorders, characterized by attention disorder, hyperactivity and disruption of circadian activity cycles. Pursuit of effective intervention strategies requires determining when the FMR1 product (FMRP) is required in the regulation of neuronal circuitry controlling these behaviors. In the well-characterized Drosophila disease model, loss of the highly conserved dFMRP causes circadian arrhythmicity and conspicuous abnormalities in the circadian clock circuitry. Here, a novel Sholl Analysis was used to quantify over-elaborated synaptic architecture in dfmr1-null small ventrolateral neurons (sLN(v)s), a key subset of clock neurons. The transgenic Gene-Switch system was employed to drive conditional neuronal dFMRP expression in the dfmr1-null mutant background in order to dissect temporal requirements within the clock circuit. Introduction of dFMRP during early brain development, including the stages of neurogenesis, neuronal fate specification and early pathfinding, provided no rescue of dfmr1 mutant phenotypes. Similarly, restoring normal dFMRP expression in the adult failed to restore circadian circuit architecture. In sharp contrast, supplying dFMRP during a transient window of very late brain development, wherein synaptogenesis and substantial subsequent synaptic reorganization (e. g. use-dependent pruning) occur, provided strong morphological rescue to reestablish normal sLN(v)s synaptic arbors. We conclude that dFMRP plays a developmentally restricted role in sculpting synaptic architecture in these neurons that cannot be compensated for by later reintroduction of the protein at maturity.