Morozov Alexei, Muzzio Isabel A, Bourtchouladze Rusiko, Van-Strien Niels, Lapidus Kyle, Yin DeQi, Winder Danny G, Adams J Paige, Sweatt J David, Kandel Eric R
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, 1051 Riverside Drive, New York, NY 10032, USA.
Neuron. 2003 Jul 17;39(2):309-25. doi: 10.1016/s0896-6273(03)00404-5.
Learning-induced synaptic plasticity commonly involves the interaction between cAMP and p42/44MAPK. To investigate the role of Rap1 as a potential signaling molecule coupling cAMP and p42/44MAPK, we expressed an interfering Rap1 mutant (iRap1) in the mouse forebrain. This expression selectively decreased basal phosphorylation of a membrane-associated pool of p42/44MAPK, impaired cAMP-dependent LTP in the hippocampal Schaffer collateral pathway induced by either forskolin or theta frequency stimulation, decreased complex spike firing, and reduced the p42/44MAPK-mediated phosphorylation of the A-type potassium channel Kv4.2. These changes correlated with impaired spatial memory and context discrimination. These results indicate that Rap1 couples cAMP signaling to a selective membrane-associated pool of p42/44MAPK to control excitability of pyramidal cells, the early and late phases of LTP, and the storage of spatial memory.
学习诱导的突触可塑性通常涉及环磷酸腺苷（cAMP）与p42/44丝裂原活化蛋白激酶（p42/44MAPK）之间的相互作用。为了研究Rap1作为连接cAMP和p42/44MAPK的潜在信号分子的作用，我们在小鼠前脑表达了一种干扰性Rap1突变体（iRap1）。这种表达选择性地降低了与膜相关的p42/44MAPK池的基础磷酸化水平，损害了由福斯高林或θ频率刺激诱导的海马体谢弗侧支通路中的cAMP依赖性长时程增强（LTP），减少了复合锋电位发放，并降低了p42/44MAPK介导的A型钾通道Kv4.2的磷酸化。这些变化与空间记忆受损和情境辨别能力下降相关。这些结果表明，Rap1将cAMP信号传导与p42/44MAPK的一个选择性膜相关池相连接，以控制锥体细胞的兴奋性、LTP的早期和晚期阶段以及空间记忆的存储。
