An EJC Factor RBM8a Regulates Anxiety Behaviors
An EJC Factor RBM8a Regulates Anxiety Behaviors
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DOI：
10.2174/15665240113139990019
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发表时间：
2013-07-01
影响因子：
2.5
通讯作者：
Mao, Y.
中科院分区：
文献类型：
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作者：
Alachkar, A.;Jiang, D.;Mao, Y.
神经可塑性依赖于基因表达的精确时机，这就需要准确控制mRNA的稳定性，并迅速消除异常的mRNA。无意义介导的信使核糖核酸衰变(NMD)是一种RNA监测机制，可确保携带提前终止密码子(PTCs)的mRNAs快速降解。这种机制依赖于几个关键的外显子连接复合体(EJC)因子来区分PTC和正常的终止密码子。NMD不仅降解携带PTCs的异常转录本，而且还降解含有正常终止密码子的正常转录本[1]。有趣的是，在自闭症患者中发现了NMD因子Upf3b的突变[2，3]。Upf3b的结合伙伴RBM8a位于1q21.1拷贝数变异(CNV)，与智力低下、自闭症[4]、精神分裂症[5]和小头畸形[6]有关。然而，EJC因子的功能及其在行为调控中的作用仍不清楚。RBM8a蛋白是EJC的核心成分，在NMD中起着重要作用。最近的遗传学研究表明，RBM8a功能获得与智力残疾显著相关。在这项研究中，我们研究了RBM8a过表达对小鼠情感行为的影响。将表达RBM8a的慢病毒注入成年小鼠的海马区，进行社会交往、开阔场地、高架迷宫和强迫游泳等行为研究。结果表明，RBM8a在小鼠齿状回(DG)的过度表达导致焦虑样行为增加，社会交往异常，强迫游泳试验(FST)中不动时间减少。为了研究其潜在的机制，我们发现在培养的原代神经元中过表达RBM8a会导致微小兴奋性突触后电流(MEPSCs)的频率显著升高。为了探讨RBM8a介导的行为改变的潜在机制，RNA免疫沉淀(RNA-IP)检测到RBM8a与CaMK2、GluR1和Egr1mRNA结合，提示RBM8a可能针对神经元基因来调节行为。这是第一项证明RBM8a在小鼠情绪行为中的关键作用的研究。这些结果揭示了NMD调节行为的新的神经机制，并潜在地提供了对精神障碍潜在的病理生理学的更好理解。
Neuroplasticity depends on the precise timing of gene expression, which requires accurate control of mRNA stability and rapid elimination of abnormal mRNA. Nonsense-mediated mRNA decay (NMD) is an RNA surveillance mechanism that ensures the speedy degradation of mRNAs carrying premature termination codons (PTCs). This mechanism relies on several key Exon Junction Complex (EJC) factors to distinguish PTCs from normal stop codons. NMD degrades not only aberrant transcripts carrying PTCs, but also normal transcripts harboring a normal stop codon [1]. Intriguingly, mutations in an NMD factor, Upf3b, have been found in patients with autism [2, 3]. A binding partner of Upf3b, RBM8a, is located in the 1q21.1 copy-number variation (CNV) associated with mental retardation, autism [4], schizophrenia [5], and microcephaly [6]. However, the functions of EJC factors and their roles in behavioral regulation are still elusive. RBM8a protein is a core component of the EJC that plays an important role in NMD. Recent genetic study indicated that RBM8a gain-of-function significantly associated with intellectual disability [7]. In this study we investigated the effect of RBM8a overexpression on affective behaviors in mice. Lentivirus expressing RBM8a was infused into the hippocampus of adult mice to conduct behavioral studies including social interaction, open field, elevated plus maze, and forced swimming tests. Our results showed that overexpression of RBM8a in the mouse dentate gyrus (DG) leads to increased anxiety-like behavior, abnormal social interaction and decreased immobile time in forced swimming test (FST). To examine the underlying mechanism, we found that overexpressing RBM8a in cultured primary neurons lead to significant higher frequency of miniature excitatory postsynaptic currents (mEPSCs). To explore the underlying mechanism of RBM8a mediated behavioral changes, RNA-immunoprecipitation (RNA-IP) detected that RBM8a binds to CaMK2, GluR1 and Egr1 mRNA, suggesting that RBM8a may target neuronal genes to regulate behaviors. This is the first study that demonstrates the key role of RBM8a on the emotional behaviors in mice. These results reveal new neural mechanisms by which NMD modulates behaviors and potentially provide a better understanding of pathophysiology underlying psychiatric disorders.