Department of Physiology, National University of Singapore, Singapore City, Singapore.
Life Sciences Institute Neurobiology Programme, National University of Singapore, Singapore City, Singapore.
Aging Cell. 2021 Feb;20(2):e13305. doi: 10.1111/acel.13305. Epub 2021 Jan 15.
The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal-dependent long-term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age-related decline. The p75 neurotrophin receptor (p75 ) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age-related alterations. However, the mechanisms by which p75 affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75 were resistant to age-associated changes in long-term plasticity, associative plasticity, and associative memory. Our study shows that p75 is responsible for age-dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA-ROCK2-LIMK1-cofilin. p75 may thus represent an important therapeutic target for limiting the age-related memory and cognitive function deficits.
在衰老过程中，对学习和记忆很重要的神经系统可塑性机制受到了极大的影响。值得注意的是，海马依赖性长期可塑性及其关联可塑性，如突触标记和捕获（STC），表现出与年龄相关的显著下降。p75 神经营养素受体（p75）是大脑结构和功能可塑性的负调节剂，因此代表了介导与年龄相关的改变的潜在候选物。然而，p75 影响老年神经元网络突触可塑性并最终导致认知功能缺陷的机制尚未得到很好的描述。在这里，我们报告说，缺乏 p75 的突变小鼠对长期可塑性、关联可塑性和关联记忆的与年龄相关的变化具有抗性。我们的研究表明，p75 通过调节几种信号通路，包括 BDNF、MAPK、Arc 和 RhoA-ROCK2-LIMK1-cofilin，负责海马体的稳态可塑性的与年龄相关的破坏。因此，p75 可能代表限制与年龄相关的记忆和认知功能缺陷的重要治疗靶标。
