Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.
Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling.
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DOI：
10.1523/jneurosci.5236-10.2011
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发表时间：
2011-01-05
期刊：
影响因子：
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通讯作者：
Zhang HT
中科院分区：
文献类型：
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作者：
Li YF;Cheng YF;Huang Y;Conti M;Wilson SP;O'Donnell JM;Zhang HT
磷酸二酯酶-4（PDE 4）通过控制细胞内环AMP（cAMP）信号传导在介导记忆中起重要作用;抑制PDE 4可增强记忆。然而，PDE 4抑制剂作为记忆增强剂的开发受到其主要副作用呕吐的阻碍。PDE 4有四种亚型（PDE 4A-D），由25种剪接变体组成。PDE 4D缺陷的小鼠在径向臂迷宫、水迷宫和物体识别测试中表现出记忆增强。这些作用通过在野生型小鼠中重复使用咯利普兰进行治疗来模拟。此外，与接受咯利普兰治疗的野生型小鼠相似，PDE 4D缺陷小鼠也显示海马神经发生和磷酸化cAMP反应元件结合蛋白（pCREB）增加。此外，将含有靶向长型PDE 4D亚型的微小RNA（miRNA）的慢病毒载体微输注到小鼠海马的双侧齿状回中下调PDE 4D 4和PDE 4D 5，增强记忆，并增加海马神经发生和pCREB。最后，虽然咯利普兰和PDE 4D缺乏缩短了α 2肾上腺素能受体介导的麻醉，但海马中miRNA介导的PDE 4D敲低并没有缩短。目前的结果表明，PDE 4D，特别是长型PDE 4D，在记忆和海马神经发生的介导中起着关键作用，这是由cAMP/CREB信号传导介导的;海马中PDE 4D，至少PDE 4D 4和PDE 4D 5的表达减少，增强记忆，但似乎不会引起呕吐。这些新的发现将有助于开发PDE 4亚型或变体选择性抑制剂，用于治疗涉及认知受损的疾病，包括阿尔茨海默病。
Phosphodiesterase-4 (PDE4) plays an important role in mediating memory via the control of intracellular cyclic AMP (cAMP) signaling; inhibition of PDE4 enhances memory. However, development of PDE4 inhibitors as memory enhancers has been hampered by their major side effect of emesis. PDE4 has four subtypes (PDE4A-D), consisting of 25 splice variants. Mice deficient in PDE4D displayed memory enhancement in radial-arm maze, water-maze, and object recognition tests. These effects were mimicked by repeated treatment with rolipram in wild-type mice. In addition, similar to rolipram-treated wild-type mice, PDE4D-deficient mice also displayed increased hippocampal neurogenesis and phosphorylated cAMP-response element binding protein (pCREB). Further, microinfusion of lentiviral vectors, which contained microRNAs (miRNAs) targeting long-form PDE4D isoforms, into bilateral dentate gyri of the mouse hippocampus down-regulated PDE4D4 and PDE4D5, enhanced memory, and increased hippocampal neurogenesis and pCREB. Finally, while rolipram and PDE4D-deficiency shortened alpha2 adrenergic receptor-mediated anesthesia, a surrogate measure of emesis, miRNA-mediated PDE4D knockdown in the hippocampus did not. The present results suggest that PDE4D, in particular long-form PDE4Ds, plays a critical role in the mediation of memory and hippocampal neurogenesis, which are mediated by cAMP/CREB signaling; reduced expression of PDE4D, at least PDE4D4 and PDE4D5, in the hippocampus enhances memory but appears not to cause emesis. These novel findings will aid in the development of PDE4 subtype- or variant-selective inhibitors for treatment of disorders involving impaired cognition, including Alzheimer’s disease.