PDF(Pubmed)
Abstract：
The disconnection of neuronal circuitry through synaptic loss is presumed to be a major driver of age-related cognitive decline. Age-related cognitive decline is heterogeneous, yet whether genetic mechanisms differentiate successful from unsuccessful cognitive decline through maintenance or vulnerability of synaptic connections remains unknown. Previous work using rodent and primate models leveraged various techniques to imply that age-related synaptic loss is widespread on pyramidal cells in prefrontal cortex (PFC) circuits but absent on those in area CA1 of the hippocampus. Here, we examined the effect of aging on synapses on projection neurons forming a hippocampal-cortico-thalamic circuit important for spatial working memory tasks from two genetically distinct mouse strains that exhibit susceptibility (C57BL/6J) or resistance (PWK/PhJ) to cognitive decline during aging. Across both strains, synapse density on CA1-to-PFC projection neurons appeared completely intact with age. In contrast, we found synapse loss on PFC-to-nucleus reuniens (RE) projection neurons from aged C57BL/6J but not PWK/PhJ mice. Moreover, synapses from aged PWK/PhJ mice but not from C57BL/6J exhibited altered morphologies that suggest increased efficiency to drive depolarization in the parent dendrite. Our findings suggest resistance to age-related cognitive decline results in part by age-related synaptic adaptations, and identification of these mechanisms in PWK/PhJ mice could uncover new therapeutic targets for promoting successful cognitive aging and extending human health span.
摘要：
通过突触丢失的神经元回路的断开被认为是与年龄相关的认知衰退的主要驱动因素。与年龄相关的认知衰退是异质的，然而，遗传机制是否通过突触连接的维持或脆弱性将成功的认知能力下降与不成功的认知能力下降区分开来仍然未知。先前使用啮齿动物和灵长类动物模型的工作利用了各种技术来暗示与年龄相关的突触损失在前额叶皮层（PFC）回路的锥体细胞上很普遍，但在海马CA1区却没有。这里,我们研究了衰老对投射神经元突触的影响,该神经元形成了对空间工作记忆任务重要的海马-皮质-丘脑回路,这两种小鼠在衰老过程中表现出对认知衰退的易感性(C57BL/6J)或抗性(PWK/PhJ).在这两种菌株中，随着年龄的增长，CA1到PFC投射神经元的突触密度似乎完全完整。相比之下,我们发现了来自老年C57BL/6J的PFC-至细胞核（RE）投射神经元的突触丢失，而不是PWK/PhJ小鼠。此外，来自老年PWK/PhJ小鼠而不是C57BL/6J的突触表现出改变的形态，表明提高了驱动亲本树突去极化的效率。我们的研究结果表明，抵抗与年龄相关的认知能力下降的部分原因是与年龄相关的突触适应，在PWK/PhJ小鼠中识别这些机制可以发现新的治疗靶标，以促进成功的认知衰老和延长人类健康范围。
