The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.
The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.
复制标题
DOI：
10.1038/tp.2014.16
复制
发表时间：
2014-03-25
影响因子：
6.8
通讯作者：
Kittler JT
中科院分区：
文献类型：
--
作者：
Pathania M;Davenport EC;Muir J;Sheehan DF;López-Doménech G;Kittler JT
15q11.2区域的拷贝数变异（CNV）已被确定为神经系统和神经精神疾病（如精神分裂症（SCZ）和自闭症谱系障碍（ASD））的重要风险位点。然而，在神经系统发育，功能和连接的基因在这个位点的个人角色仍然知之甚少。在这个区域的一个基因，Cyfip 1，单倍不足，可能提供了一个模型，15q11.2 CNV相关的神经精神表型。在这里，我们表明，在体外和体内改变神经元中CYFIP 1的表达水平影响树突的复杂性，棘形态，棘肌动蛋白动力学和突触α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的横向扩散。CYFIP 1在突触处高度富集，并且其在体外的过表达导致树突复杂性增加。另一方面，来自Cyfip 1杂合动物的神经元具有降低的树突复杂性、增加的移动的F-肌动蛋白和增强的含GluA 2的AMPA受体在突触处的移动性。有趣的是，Cyfip 1过表达或单倍不足增加未成熟的脊髓数量，而脊髓体积的活动依赖性变化被闭塞在Cyfip 1单倍不足的神经元。在体内，Cyfip 1杂合子动物表现出的缺陷，树突的复杂性，以及海马CA 1神经元的未成熟到成熟的棘的比例改变。总之，我们提供的证据表明，CYFIP 1表达水平失调导致CNS成熟和神经元连接的病理变化，这两者都可能有助于ASD和SCZ中神经系统症状的发展。
Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.