Major Vault Protein, a Candidate Gene in 16p11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity
Major Vault Protein, a Candidate Gene in 16p11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity
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DOI：
10.1523/jneurosci.2034-17.2018
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发表时间：
2018-04-18
影响因子：
5.3
通讯作者：
Sur, Mriganka
中科院分区：
文献类型：
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作者：
Ip, Jacque P. K.;Nagakura, Ikue;Sur, Mriganka
染色体16p11.2区域的微缺失增加了自闭症的易感性。虽然这个区域包含29个基因的外显子，但只要破坏该区域的一小部分，即跨越5个基因，就足以导致自闭症特征。这个关键片段中的一个候选基因是MVP，其编码与细胞转运机制调控有关的主要穹窿蛋白（MVP）。MVP+/-小鼠的MVP表达水平与16p11.2突变小鼠的MVP表达水平非常接近，这表明MVP+/-小鼠可以作为16p11.2微缺失中MVP功能的模型。在这里，我们表明，MVP调节眼优势（OD）可塑性在初级视觉皮层的稳态成分。两种性别的MVP+/-小鼠在单眼剥夺（MD）数天后显示睁眼反应的增强受损，而闭眼反应正常减弱，导致总体OD可塑性降低。在MVP+/-小鼠中，延长MD后锥体神经元中的微型EPSC（mEPSC）的频率降低，表明功能性突触减少。相应地，MVP+/-小鼠在延长MD后，表面GluA 1 AMPA受体的上调减少，并伴随着STAT 1和磷酸化ERK表达的改变，这与OD可塑性有关。通过引入STAT 1 shRNA使STAT 1水平正常化，挽救了表面GluA 1和睁眼反应，暗示STAT 1是MVP的下游效应子。这些研究结果表明，MVP作为一个关键分子影响的稳态成分的活动依赖性突触可塑性，并可能相应的16p11.2微缺失综合征的表型的特定作用。
Microdeletion of a region in chromosome 16p11.2 increases susceptibility to autism. Although this region contains exons of 29 genes, disrupting only a small segment of the region, which spans five genes, is sufficient to cause autistic traits. One candidate gene in this critical segment is MVP, which encodes for the major vault protein (MVP) that has been implicated in regulation of cellular transport mechanisms. MVP expression levels in MVP+/- mice closely phenocopy those of 16p11.2 mutant mice, suggesting that MVP+/- mice may serve as a model ofMVPfunction in 16p11.2 microdeletion. Here we show thatMVPregulates the homeostatic component of ocular dominance (OD) plasticity in primary visual cortex. MVP+/- mice of both sexes show impairment in strengthening of open-eye responses after several days of monocular deprivation (MD), whereas closed-eye responses are weakened as normal, resulting in reduced overallODplasticity. The frequency of miniature EPSCs (mEPSCs) in pyramidal neurons is decreased in MVP+/- mice after extendedMD, suggesting a reduction of functional synapses. Correspondingly, upregulation of surface GluA1 AMPA receptors is reduced in MVP+/- mice after extended MD, and is accompanied by altered expression of STAT1 and phosphorylated ERK, which have been previously implicated inODplasticity. Normalization of STAT1 levels by introducing STAT1 shRNA rescues surface GluA1 and open-eye responses, implicating STAT1 as a downstream effector of MVP. These findings demonstrate a specific role for MVP as a key molecule influencing the homeostatic component of activity-dependent synaptic plasticity, and potentially the corresponding phenotypes of 16p11.2 microdeletion syndrome.