Knock-down of PQBP1 impairs anxiety-related cognition in mouse
Knock-down of PQBP1 impairs anxiety-related cognition in mouse
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DOI：
10.1093/hmg/ddp378
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发表时间：
2009-11-15
影响因子：
3.5
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
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作者：
Ito, Hikaru;Yoshimura, Natsue;Okazawa, Hitoshi
PQBP1(聚谷氨酰胺结合蛋白1)是一种相对常见的X连锁综合征和非综合征智力低下(MR)的致病基因。为了从分子基础上分析这些患者的行为异常，我们建立了一个击倒(KD)小鼠模型。KD小鼠具有表达498bp双链RNA的转基因，该双链RNA内源切割成siRNA，有效地抑制PQBP1。在确认PQBP1被选择性抑制到近50%的对照组小鼠之后，我们对PQBP1-KD小鼠进行了行为分析。KD小鼠在水迷宫等常规记忆测验中表现出正常的记忆能力，而在明暗探索和旷场测验中表现出异常的焦虑相关行为，在重复的高架加迷宫或新物体再认实验中表现出明显的焦虑相关认知下降。相应地，在行为学测试后，我们发现杏仁核、前额叶皮质和海马神经元中c-fos上调和组蛋白H3乙酰化水平下降。此外，我们还发现HDAC抑制剂4-苯丁酸有效地促进了这些基因的表达，并挽救了成年PQBP1-KD小鼠的异常表型。这些结果提示，PQBP1基因表达调控功能障碍可能是导致PQBP1-KD小鼠行为和认知功能异常的原因，PQBP1靶基因表达的恢复可能改善成年患者的症状。
PQBP1 (polyglutamine tract-binding protein 1) is a causative gene for a relatively frequent X-linked syndromic and non-syndromic mental retardation (MR). To analyze behavioral abnormalities of these patients from molecular basis, we developed a knock-down (KD) mouse model. The KD mice possess a transgene expressing 498 bp double-strand RNA that is endogenously cleaved to siRNA suppressing PQBP1 efficiently. After confirming that PQBP1 is selectively suppressed to nearly 50% of the control mice, we performed behavioral analyses of PQBP1-KD mice. The KD mice possessed normal ability in ordinary memory tests including water-maze test, whereas they showed abnormal anxiety-related behavior in light/dark exploration test and open-field test and showed obvious declines of anxiety-related cognition in the repetitive elevated plus maze or novel object recognition test. Correspondingly, we found c-fos upregulation and histone H3 acetylation after behavior tests were declined in neurons of amygdala, prefrontal cortex and hippocampus. Furthermore, we found that 4-phenylbutyric acid, an HDAC inhibitor, efficiently improved expression of these genes and rescued the abnormal phenotypes in adult PQBP1-KD mice. These results suggested that PQBP1 dysfunction in regulating gene expression might underlie the abnormal behavior and cognition of PQBP1-KD mice and that the recovery of expression of such PQBP1 target genes might improve the symptoms in adult patients.