Genetic Dissection of Age-related Memory Impairment

虽然众所周知，衰老与记忆丧失有关，但由于缺乏与年龄相关的记忆损害(AMI)特异性突变体，导致AM I的具体分子机制尚不清楚。在此之前，我们根据失忆症(AMN)基因确定果蝇的衰老特异性地损害记忆阶段，并假设AMN下游的信号导致急性心肌梗死。在这个目前的项目中，我们通过筛选急性心肌梗死发病改变的突变和鉴定编码PKA催化亚单位的基因DC0的杂合突变来扩展这项工作，在不影响年轻年龄记忆的情况下将急性心肌梗死延迟两倍以上。此外，我们鉴定的DC0突变体没有显示出任何延长寿命的迹象，这表明急性心肌梗死可以与器官衰老分离。鉴于DC0的鉴定，我们证明了在记忆形成中重要的结构蘑菇体(MBS)中的PKA活性可以通过改变MBS中的cAMP/PKA信号活性来控制导致急性心肌梗死和急性心肌梗死的发病。值得注意的是，AMN编码的神经肽被认为是调节cAMP水平的，表达AMN的DPM细胞支配MBS。此外，amn突变体不会随着年龄的增长表现出进一步的记忆衰退。我们发现在amn；DC0/+双突变体中，amn依赖的记忆和急性心肌梗死都恢复了。这些结果表明，MBS中的cAMP/PKA信号是AMN下游的信号，并在衰老后导致急性心肌梗死。

Although it is widely known that aging is associated with memory loss, the specific molecular mechanisms that contribute to age-related memory impairment (AMI) are unknown, because of a lack of AMI-specific mutants. Previously, we determined that Drosophila aging specifically impairs memory phase depending on amnesiac (amn), gene encoding putative neuropeptides, and hypothesized that signaling downstream of amn leads to AMI. In this current project, we extend this work by screening for mutants with altered AMI onset and identifying that heterozygous mutations in DC0, the gene encoding the catalytic subunit of PKA, delay AMI more than two fold without affecting memory at young ages. Furthermore, our identified DC0 mutants do not show any increases in longevity, demonstrating that AMI can be dissociated from organismal aging. Given the identification of DC0, we demonstrate that PKA activity in the mushroom bodies (MBs), structures important in memory formation, causes AMI and AMI onset can be controlled by altering cAMP/PKA signaling activity in the MBs. Notably, putative neuropeptides encoded by amn are proposed to regulate cAMP level, and DPM cells expressing amn innervate MBs. In addition, amn mutants do not show further memory decay upon aging. We show here that both amn-dependent memory and AMI are restored in amn ; DC0/+ double mutants. These results suggest that cAMP/PKA signaling in the MBs is a downstream of amn and leads to AMI upon aging.