Lu Yubing, Lu Yi-Sheng, Shuai Yichun, Feng Chunhua, Tully Tim, Xie Zuoping, Zhong Yi, Zhou Hai-Meng
Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.
Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13792-7. doi: 10.1073/pnas.0700439104. Epub 2007 Aug 9.
Extensive neurogenetic analysis has shown that memory formation depends critically on cAMP-protein kinase A (PKA) signaling. Details of how this pathway is involved in memory formation, however, remain to be fully elucidated. From a large-scale behavioral screen in Drosophila, we identified the yu mutant to be defective in one-day memory after spaced training. The yu mutation disrupts a gene encoding an A-kinase anchoring protein (AKAP). AKAPs comprise a family of proteins, which determine the subcellular localization of PKAs and thereby critically restrict cAMP signaling within a cell. Further behavioral characterizations revealed that long-term memory (LTM) was disrupted specifically in the yu mutant, whereas learning, short-term memory and anesthesia-resistant memory all appeared normal. Another independently isolated mutation of the yu gene failed to complement the LTM defect associated with the yu mutation, and this phenotypic defect could be rescued by induced acute expression of a yu(+) transgene, suggesting that yu functions physiologically during memory formation. AKAP Yu is expressed preferentially in the mushroom body (MB) neuroanatomical structure, and expression of a yu(+) transgene to the MB, but not to other brain regions, is sufficient to rescue the LTM defect of the yu mutant. These observations lead us to conclude that proper localization of PKA by Yu AKAP in MB neurons is required for the formation of LTM.
广泛的神经遗传学分析表明，记忆形成关键依赖于环磷酸腺苷-蛋白激酶A（PKA）信号通路。然而，该通路如何参与记忆形成的细节仍有待充分阐明。通过对果蝇的大规模行为筛选，我们发现yu突变体在间隔训练后的一天记忆方面存在缺陷。yu突变破坏了一个编码A激酶锚定蛋白（AKAP）的基因。AKAPs构成了一个蛋白质家族，它们决定了PKA的亚细胞定位，从而严格限制细胞内的环磷酸腺苷信号传导。进一步的行为特征分析表明，长期记忆（LTM）在yu突变体中特异性地受到破坏，而学习、短期记忆和抗麻醉记忆均表现正常。另一个独立分离的yu基因突变不能弥补与yu突变相关的LTM缺陷，并且这种表型缺陷可以通过诱导yu（+）转基因的急性表达来挽救，这表明yu在记忆形成过程中发挥生理功能。AKAP Yu在蘑菇体（MB）神经解剖结构中优先表达，将yu（+）转基因表达于MB而非其他脑区足以挽救yu突变体的LTM缺陷。这些观察结果使我们得出结论，MB神经元中Yu AKAP对PKA的正确定位是LTM形成所必需的。
