Delayed stabilization of dendritic spines in fragile X mice.
Delayed stabilization of dendritic spines in fragile X mice.
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DOI：
10.1523/jneurosci.0577-10.2010
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发表时间：
2010-06-09
期刊：
影响因子：
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通讯作者：
Portera-Cailliau C
中科院分区：
文献类型：
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作者：
Cruz-Martín A;Crespo M;Portera-Cailliau C
脆性X综合征（FXS）通过Fmr 1基因的转录沉默导致RNA结合蛋白FMRP的丢失，从而导致精神障碍和自闭症。受影响个体和Fmr 1敲除（KO）小鼠的皮质锥体神经元树突棘密度增加。突变小鼠还表现出突触和经验依赖性回路可塑性的缺陷，已知这部分是由树突棘动力学介导的。我们使用体内延时成像与2-光子显微镜通过颅窗在男性和女性新生小鼠测试的假设，即动态的树突状突起在KO小鼠出生后早期发育过程中改变。我们发现，从野生型小鼠的第2/3层神经元表现出迅速减少树突棘动力学在出生后的头两个星期，不成熟的丝状伪足和原棘取代蘑菇刺。相比之下，KO小鼠在脊椎转换的下调和从未成熟到成熟脊椎亚型的转变中显示发育延迟。阻断代谢型谷氨酸受体（mGluR）信号传导，逆转了KO小鼠的一些成年表型，加重了KO小鼠的这种不成熟突起表型。因此，FMRP的缺乏延迟了脊柱稳定性，并且FXS中失调的mGluR信号传导可以部分地使这种早期突触缺陷正常化。
Fragile X syndrome (FXS) causes mental impairment and autism through transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein FMRP. Cortical pyramidal neurons in affected individuals and Fmr1 knockout (KO) mice have an increased density of dendritic spines. The mutant mice also show defects in synaptic and experience-dependent circuit plasticity, which are known to be mediated in part by dendritic spine dynamics. We used in vivo time-lapse imaging with 2-photon microscopy through cranial windows in male and female neonatal mice to test the hypothesis that dynamics of dendritic protrusions are altered in KO mice during early postnatal development. We find that layer 2/3 neurons from wild type mice exhibit a rapid decrease in dendritic spines dynamics during the first two postnatal weeks, as immature filopodia and protospines are replaced by mushroom spines. In contrast, KO mice show a developmental delay in the downregulation of spine turnover and in the transition from immature to mature spine subtypes. Blockade of metabotropic glutamate receptor (mGluR) signaling, which reverses some adult phenotypes of KO mice, accentuated this immature protrusion phenotype in KO mice. Thus, absence of FMRP delays spine stabilization and dysregulated mGluR signaling in FXS may partially normalize this early synaptic defect.