Genetic Dissection of Age-related Memory Impairment

年龄相关记忆障碍的基因剖析

基本信息

批准号：
16300107
负责人：
SAITOE Minoru
金额：
$ 9.47万
依托单位：
Tokyo Metropolitan Organization for Medical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300107/
关键词：
Learning and Memory PKA Aging Mutant Molecular Mechanism 遺伝子ショウジョウバエ学主記憶

项目摘要

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.

尽管众所周知，衰老与记忆丧失有关，但由于缺乏 AMI 特异性突变体，导致年龄相关记忆障碍 (AMI) 的具体分子机制尚不清楚。此前，我们确定果蝇衰老会根据遗忘症（amn）（编码推定神经肽的基因）特异性损害记忆阶段，并假设 amn 下游信号传导导致 AMI。在当前的项目中，我们通过筛选 AMI 发病发生改变的突变体并鉴定 DC0（编码 PKA 催化亚基的基因）中的杂合突变来扩展这项工作，使 AMI 延迟两倍以上，而不影响年轻时的记忆力。此外，我们发现的 DC0 突变体没有表现出任何寿命延长，这表明 AMI 可以与机体衰老无关。鉴于 DC0 的鉴定，我们证明蘑菇体 (MB)（记忆形成中重要的结构）中的 PKA 活性会导致 AMI，并且可以通过改变 MB 中的 cAMP/PKA 信号活性来控制 AMI 发作。值得注意的是，推测由 amn 编码的神经肽可调节 cAMP 水平，表达 amn 的 DPM 细胞可神经支配 MB。此外，amn 突变体在衰老时不会表现出进一步的记忆衰退。我们在这里展示了 amn 相关的记忆和 AMI 都在 amn 中恢复； DC0/+双突变体。这些结果表明，MB 中的 cAMP/PKA 信号传导是 amn 的下游，并在衰老时导致 AMI。