Altered Hippocampal Transcript Profile Accompanies an Age-Related Spatial Memory Deficit in Mice

We have carried out a global survey of age-related changes in mRNA levels in the C57BL/6NIA mouse hippocampus and found a difference in the hippocampal gene expression profile between 2-month-old young mice and 15-month-old middle-aged mice correlated with an age-related cognitive deficit in hippocampal-based explicit memory formation. Middle-aged mice displayed a mild but specific deficit in spatial memory in the Morris water maze. By using Affymetrix GeneChip microarrays, we found a distinct pattern of age-related change, consisting mostly of gene overexpression in the middle-aged mice, suggesting that the induction of negative regulators in the middle-aged hippocampus could be involved in impairment of learning. Interestingly, we report changes in transcript levels for genes that could affect synaptic plasticity. Those changes could be involved in the memory deficits we observed in the 15-month-old mice. In agreement with previous reports, we also found altered expression in genes related to inflammation, protein processing, and oxidative stress.

我们针对C57BL/6NIA小鼠（C57BL/6NIA mouse）海马体（hippocampus）内mRNA（messenger RNA）水平的增龄性变化开展了全基因组筛查，发现2月龄青年小鼠与15月龄中年小鼠的海马基因表达谱存在显著差异，该差异与依赖海马体的外显记忆形成过程中出现的年龄相关性认知缺陷密切相关。中年小鼠在莫里斯水迷宫（Morris water maze）实验中表现出轻度但具有特异性的空间记忆缺陷。通过Affymetrix GeneChip微阵列（Affymetrix GeneChip microarrays）技术，我们观测到了独特的增龄性基因表达模式：中年小鼠体内以基因过表达（gene overexpression）为主要特征，这提示中年海马体中负调控因子的诱导上调或许参与了学习能力的受损过程。值得注意的是，我们发现若干可影响突触可塑性（synaptic plasticity）的基因的转录水平发生改变，此类变化或与15月龄小鼠所观测到的记忆缺陷存在关联。与既往研究报道一致，我们还检测到与炎症（inflammation）、蛋白质加工（protein processing）及氧化应激（oxidative stress）相关的基因表达出现异常改变。