Cyfip1 Regulates Presynaptic Activity during Development
Cyfip1 Regulates Presynaptic Activity during Development
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DOI：
10.1523/jneurosci.0511-15.2016
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发表时间：
2016-02-03
影响因子：
5.3
通讯作者：
Benson, Deanna L.
中科院分区：
文献类型：
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作者：
Hsiao, Kuangfu;Harony-Nicolas, Hala;Benson, Deanna L.
包含编码Cyfip 1的基因的拷贝数变异与多种人类疾病有关，包括自闭症和精神分裂症。在这里，我们表明，青少年小鼠半合子Cyfip 1改变了突触前功能，增强蛋白质翻译，并增加F-肌动蛋白的水平。在发育中的海马中，降低Cyfip 1水平有助于减少成对脉冲易化，并增加微型EPSC频率而不改变振幅。更高分辨率的检查表明，这些变化主要是由突触前末端尺寸的增加和囊泡释放概率的增强引起的。短发夹介导的敲除Cyfip 1加上突变Cyfip 1蛋白的表达表明突触前改变是由WAVE调节复合物的失调引起的。这种失调发生在Rac 1的下游，因为急性暴露于Rac 1抑制剂可以挽救培养物和海马切片中的突触前反应。这些数据突出了Cyfip 1在正常功能突触生成中的早期和重要作用，并提出了Cyfip 1水平变化可能影响神经网络生成并导致异常和适应不良行为的方法。
Copy number variations encompassing the gene encoding Cyfip1 have been associated with a variety of human diseases, including autism and schizophrenia. Here we show that juvenile mice hemizygous for Cyfip1 have altered presynaptic function, enhanced protein translation, and increased levels of F-actin. In developing hippocampus, reduced Cyfip1 levels serve to decrease paired pulse facilitation and increase miniature EPSC frequency without a change in amplitude. Higher-resolution examination shows these changes to be caused primarily by an increase in presynaptic terminal size and enhanced vesicle release probability. Short hairpin-mediated knockdown of Cyfip1 coupled with expression of mutant Cyfip1 proteins indicates that the presynaptic alterations are caused by dysregulation of the WAVE regulatory complex. Such dysregulation occurs downstream of Rac1 as acute exposure to Rac1 inhibitors rescues presynaptic responses in culture and in hippocampal slices. The data serve to highlight an early and essential role for Cyfip1 in the generation of normally functioning synapses and suggest a means by which changes in Cyfip1 levels could impact the generation of neural networks and contribute to abnormal and maladaptive behaviors.