Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical School, Durham, North Carolina, 27710, USA.
J Neurosci. 2013 Apr 3;33(14):6081-92. doi: 10.1523/JNEUROSCI.0035-13.2013.
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 knock-out 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.
尽管有证据表明，几种主要精神疾病与强烈的遗传因素有关，但单个候选基因仅能解释这些疾病的一小部分，这表明可能涉及多种遗传途径。几种已知的精神疾病遗传风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着关键作用。为了深入了解和测试该途径的可能致病作用，我们设计了一种 Arp2/3 复合物的条件敲除，该复合物是肌动蛋白信号通路的保守终产物，可协调新的肌动蛋白聚合。在这里，我们报告说，大脑前兴奋性神经元中 Arp2/3 亚基 ArpC3 的出生后缺失导致树突棘的不对称结构可塑性，随后是棘突触的逐渐丧失。随着年龄的增长，这种突触缺陷的进展与认知、精神运动和社会障碍的不同演变相对应。总之，这些结果表明肌动蛋白信号转导的功能障碍，特别是汇聚调节 Arp2/3 的信号转导功能障碍，可能是导致复杂精神疾病病因的重要细胞途径。
