Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome
Altered dendritic spine function and integration in a mouse model of Fragile X Syndrome
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脆性 X 综合征小鼠模型中树突棘功能和整合的改变
DOI：
10.1101/396986
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Booker S
中科院分区：
文献类型：
--
作者：
Booker S
细胞和电路的过度兴奋是脆性X综合征和相关自闭症谱系障碍模型的核心特征。然而，这种过度兴奋的细胞和突触基础已经被证明是难以捉摸的。我们在脆性X综合征的小鼠模型中报告，谷氨酸释放到单个树突棘上产生比野生型更强的单棘兴奋，具有更多的沉默棘。此外，需要较少的棘来触发动作电位，其中在多个棘处几乎同时解除锁定。这部分是由于固有兴奋性增加导致的树突增益增加，这是由超极化激活电流减少和NMDA受体信号传导增加引起的。使用超分辨率显微镜，我们检测到树突棘形态没有变化，表明在这个年龄没有结构-功能关系。然而，超微结构分析显示，在多神经支配的脊柱增加3倍，占增加的单棘谷氨酸电流。因此，FMRP的丢失导致异常的突触发生，导致大量的多突触棘，尽管正常的棘形态，从而解释了潜在的电路超兴奋性的突触扰动。
Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines. Furthermore, fewer spines are required to trigger an action potential with near-simultaneous uncaging at multiple spines. This is, in part, from increased dendritic gain due to increased intrinsic excitability, resulting from reduced hyperpolarization-activated currents, and increased NMDA receptor signaling. Using super-resolution microscopy we detect no change in dendritic spine morphology, indicating no structure-function relationship at this age. However, ultrastructural analysis shows a 3-fold increase in multiply-innervated spines, accounting for the increased single-spine glutamate currents. Thus, loss of FMRP causes abnormal synaptogenesis, leading to large numbers of poly-synaptic spines despite normal spine morphology, thus explaining the synaptic perturbations underlying circuit hyperexcitability.