Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.
Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease.
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DOI：
10.1038/nature17172
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发表时间：
2016-03-24
期刊：
影响因子：
64.8
通讯作者：
Tonegawa S
中科院分区：
文献类型：
--
作者：
Roy DS;Arons A;Mitchell TI;Pignatelli M;Ryan TJ;Tonegawa S
阿尔茨海默病（Alzheimer's disease，AD）是一种以进行性记忆衰退和随后的广泛认知功能丧失为特征的神经退行性疾病。阿尔茨海默氏症早期的记忆衰退主要限于情景记忆，海马体（HPC）在其中起着至关重要的作用。然而，在阿尔茨海默氏症的早期阶段观察到的健忘症是否是由于中断的编码和整合的情节信息，或在检索存储的记忆信息的损伤，一直是不确定的。在这里，我们表明，在早期阿尔茨海默氏症的转基因小鼠模型中，海马记忆印迹细胞的直接光遗传学激活导致记忆检索，尽管这些小鼠在利用自然回忆线索的长期记忆测试中是健忘的，揭示了检索，而不是存储障碍。在淀粉样蛋白斑块沉积之前，这些小鼠的健忘症是年龄依赖性的，这与海马齿状回（DG）印迹细胞棘密度的进行性降低相关。我们发现，光遗传学诱导的长时程增强（LTP）在穿通路径（PP）突触的DG记忆颗粒细胞恢复棘密度和长期记忆。我们还表明，消融DG印迹细胞恢复棘密度阻止救援的长期记忆。因此，选择性拯救记忆印迹细胞中的棘密度可能会导致治疗阿尔茨海默病早期记忆丧失的有效策略。
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in early stages of Alzheimer’s is mostly limited to episodic memory, for which the hippocampus (HPC) plays a crucial role. However, it has been uncertain whether the observed amnesia in early stages of Alzheimer’s is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early Alzheimer’s, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are utilized, revealing a retrieval, rather than a storage impairment. Prior to amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction of spine density of hippocampal dentate gyrus (DG) engram cells. We show that optogenetic induction of long-term potentiation (LTP) at perforant path (PP) synapses of DG engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of DG engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in early stages of Alzheimer’s disease.