Yamazaki Daisuke, Horiuchi Junjiro, Nakagami Yasuko, Nagano Shintaro, Tamura Takuya, Saitoe Minoru
Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan.
Nat Neurosci. 2007 Apr;10(4):478-84. doi: 10.1038/nn1863. Epub 2007 Feb 25.
The study of age-related memory impairment (AMI) has been hindered by a lack of AMI-specific mutants. In a screen for such mutants in Drosophila melanogaster, we found that heterozygous mutations of DCO (DCO/+), which encodes the major catalytic subunit of cAMP-dependent protein kinase (PKA), delay AMI more than twofold without affecting lifespan or memory at early ages. AMI is restored when a DCO transgene is expressed in mushroom bodies, structures important for olfactory memory formation. Furthermore, increasing cAMP and PKA activity in mushroom bodies causes premature AMI, whereas reducing activity suppresses AMI. In Drosophila AMI consists of a specific reduction in memory dependent on the amnesiac (amn) gene. amn encodes putative neuropeptides that have been proposed to regulate cAMP levels in mushroom bodies. Notably, both the memory and AMI defects of amn mutants are restored in amn;DCO/+ double mutants, suggesting that AMI is caused by an age-related disruption of amn-dependent memory via PKA activity in mushroom bodies.
由于缺乏与年龄相关的记忆损伤（AMI）特异性突变体，对AMI的研究受到了阻碍。在对黑腹果蝇中此类突变体的筛选中，我们发现，编码环磷酸腺苷（cAMP）依赖性蛋白激酶（PKA）主要催化亚基的DCO基因的杂合突变（DCO/+），可使AMI延迟两倍以上，且不影响早期的寿命或记忆。当在蘑菇体（对嗅觉记忆形成很重要的结构）中表达DCO转基因时，AMI得以恢复。此外，增加蘑菇体中的cAMP和PKA活性会导致过早出现AMI，而降低活性则会抑制AMI。在果蝇中，AMI表现为依赖失忆基因（amn）的记忆特异性降低。amn编码推测的神经肽，有人提出这些神经肽可调节蘑菇体中的cAMP水平。值得注意的是，amn突变体的记忆和AMI缺陷在amn;DCO/+双突变体中均得到恢复，这表明AMI是由蘑菇体中PKA活性导致的与年龄相关的amn依赖性记忆破坏引起的。
