A mouse model of Rubinstein-Taybi syndrome: Defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4
A mouse model of Rubinstein-Taybi syndrome: Defective long-term memory is ameliorated by inhibitors of phosphodiesterase 4
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DOI：
10.1073/pnas.1834280100
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发表时间：
2003-09-02
影响因子：
11.1
通讯作者：
Tully, T
中科院分区：
文献类型：
--
作者：
Bourtchouladze, R;Lidge, R;Tully, T
携带一种截短形式的环腺苷酸反应元件结合蛋白（CREB）结合蛋白（CBP）的小鼠表现出几种发育异常，与鲁宾斯坦 - 泰比综合征（RTS）患者相似。RTS患者患有智力障碍，而突变的CBP小鼠长期记忆形成存在缺陷。在CREB依赖性长期记忆形成过程中环腺苷酸信号传导的关键作用似乎在进化上是保守的。基于这一观察结果，我们推断通过增强环腺苷酸信号传导来调节CREB功能的药物可能对CBP+/-小鼠的记忆缺陷产生有效的治疗作用。为此，我们设计了一种基于细胞的药物筛选，发现磷酸二酯酶4（PDE4）抑制剂是CREB功能特别有效的增强剂。我们通过展示CBP+/-突变体在物体识别任务中存在长期记忆受损但学习和短期记忆正常的情况，扩展了先前的行为观察结果。我们证明原型PDE4抑制剂咯利普兰以及一种新型抑制剂（HT0712）消除了CBP+/-小鼠的长期记忆缺陷。重要的是，CBP中的基因损伤特异性地改变了HT0712增强记忆形成的剂量敏感性，这体现了药物作用机制的分子特异性。我们的结果表明，PDE4抑制剂可用于治疗RTS患者的认知功能障碍。
Mice carrying a truncated form of cAMP-responsive element binding protein (CREB)-binding protein (CBP) show several developmental abnormalities similar to patients with Rubinstein-Taybi syndrome (RTS). RTS patients suffer from mental retardation, whereas long-term memory formation is defective in mutant CBP mice. A critical role for cAMP signaling during CREB-dependent long-term memory formation appears to be evolutionarily conserved. From this observation, we reasoned that drugs that modulate CREB function by enhancing cAMP signaling might yield an effective treatment for the memory defect(s) of CBP+/- mice. To this end, we designed a cell-based drug screen and discovered inhibitors of phosphodiesterase 4 (PDE4) to be particularly effective enhancers of CREB function. We extend previous behavioral observations by showing that CBP+/- mutants have impaired long-term memory but normal learning and short-term memory in an object recognition task. We demonstrate that the prototypical PDE4 inhibitor, rolipram, and a novel one (HT0712) abolish the long-term memory defect of CBP+/- mice. Importantly, the genetic lesion in CBP acts specifically to shift the dose sensitivity for HT0712 to enhance memory formation, which conveys molecular specificity on the drug's mechanism of action. Our results suggest that PDE4 inhibitors may be used to treat the cognitive dysfunction of RTS patients.