Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome
Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome
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Calsyntenin-1 负向调节 ICAM5 在突触后膜中的积累并影响脆性 X 综合征小鼠模型的树突棘成熟
DOI：
10.3389/fnins.2019.01098
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发表时间：
2019-10-18
影响因子：
4.3
通讯作者：
Zeng, Yan
中科院分区：
文献类型：
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作者：
Cheng, Ke;Chen, Yu-Shan;Zeng, Yan
脆性X综合征（FXS）是一种导致智力残疾的神经发育障碍，也是自闭症谱系障碍（ASD）的主要单基因原因，其中神经元显示异常的树突棘结构。由人类X连锁Fmr 1基因编码的功能性FMRP蛋白的减少/缺失是该综合征的原因。FMRP、CLSTN 1和ICAM 5的靶点在树突棘的成熟、突触形成和突触可塑性中起关键作用。然而，CLSTN 1和ICAM 5在树突棘异常和FXS中的潜在神经病理过程中的作用尚未研究。在这项研究中，我们证明了CLSTN 1与ICAM 5在培养的皮层神经元中共定位和共转运。我们还发现，在培养的WT神经元中，shRNA介导的CLSTN 1下调增加突触膜表面的ICAM 5，随后影响树突棘的成熟。然而，Fmr 1 KO神经元中CLSTN 1水平的正常化降低了ICAM 5丰度并挽救了受损的树突棘表型。最重要的是，CLSTN 1蛋白在Fmr 1基因敲除小鼠出生后内侧前额叶皮质中减少，这与突触表面ICAM 5水平增加和过度的丝状伪足样棘相关。总之，这项研究表明，CLSTN 1通过调节ICAM 5再分布在FXS中树突棘的形成和成熟中起着关键作用。
Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability, as well as the leading monogenic cause of autism spectrum disorders (ASD), in which neurons show aberrant dendritic spine structure. The reduction/absence of the functional FMRP protein, coded by the X-linked Fmr1 gene in humans, is responsible for the syndrome. Targets of FMRP, CLSTN1, and ICAM5, play critical roles in the maturation of dendritic spines, synapse formation and synaptic plasticity. However, the implication of CLSTN1 and ICAM5 in dendritic spine abnormalities and the underlying neuropathologic processes in FXS remain uninvestigated. In this study, we demonstrated that CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. Also we showed that shRNA-mediated downregulation of CLSTN1 in cultured WT neurons increases ICAM5 on the surface of synaptic membrane, subsequently affecting the maturation of dendritic spines. Whereas, normalization of CLSTN1 level in Fmr1 KO neurons reduces ICAM5 abundance and rescues impaired dendritic spine phenotypes. Most importantly, CLSTN1 protein is reduced in the postnatal medial prefrontal cortex of Fmr1 KO mice, which is correlated with increased ICAM5 levels on the surface of synapses and excessive filopodia-like spines. In conclusion, this study demonstrates that CLSTN1 plays a critical role in dendritic spine formation and maturation in FXS by regulating ICAM5 redistribution.