Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities.
Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities.
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DOI：
10.1523/jneurosci.0035-13.2013
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发表时间：
2013-04-03
期刊：
影响因子：
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通讯作者：
Soderling SH
中科院分区：
文献类型：
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作者：
Kim IH;Racz B;Wang H;Burianek L;Weinberg R;Yasuda R;Wetsel WC;Soderling SH
尽管有证据表明遗传对几种主要精神疾病有很强的影响，但单个候选基因只占这些疾病的一小部分，这导致了可能涉及多遗传途径的建议。一些已知的精神疾病的遗传危险因素与肌动蛋白聚合的调节有关，肌动蛋白聚合在突触可塑性中起关键作用。为了深入了解和测试这一途径可能的致病作用，我们设计了一种有条件敲除Arp2/3复合物的方法，Arp2/3复合物是肌动蛋白信号通路的保守最终输出，它协调了肌动蛋白的新聚合。本研究报告指出，出生后前脑兴奋性神经元中Arp2/3亚基ArpC3的缺失导致树突棘的不对称结构可塑性，随后是脊柱突触的逐渐缺失。随着小鼠年龄的增长，突触缺陷的进展与明显的认知、精神运动和社交障碍的进化相对应。综上所述，这些结果表明肌动蛋白信号的功能障碍，特别是那些聚集调节Arp2/3的信号，是一个重要的细胞通路，可能导致复杂精神疾病的病因。
Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known genetic risk factors for psychiatric disease are related to the regulation of actin polymerization, which plays a key role in synaptic plasticity. To gain insight into and test the possible pathogenetic role of this pathway, we designed a conditional knockout of the Arp2/3 complex, a conserved final output for actin signaling pathways that orchestrates de novo actin polymerization. Here we report that postnatal loss of the Arp2/3 subunit ArpC3 in forebrain excitatory neurons leads to an asymmetric structural plasticity of dendritic spines, followed by a progressive loss of spine synapses. This progression of synaptic deficits corresponds with an evolution of distinct cognitive, psychomotor, and social disturbances as the mice age. Together these results point to the dysfunction of actin signaling, specifically that which converges to regulate Arp2/3, as an important cellular pathway that may contribute to the etiology of complex psychiatric disorders.