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Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

2016; Nature Portfolio; Volume: 531; Issue: 7595 Linguagem: Inglês

10.1038/nature17172

1476-4687

Dheeraj S. Roy, Autumn L. Arons, Teryn Mitchell, Michele Pignatelli, Tomás J. Ryan, Susumu Tonegawa,

Neuroscience and Neuropharmacology Research

Experiments in transgenic mouse models of early Alzheimer’s disease show that the amnesia seen at this stage of the disease is probably caused by a problem with memory retrieval from the hippocampus rather than an encoding defect. The hippocampus plays a crucial role in the encoding, consolidation, and retrieval of episodic memories, which are the first to go missing in the early stages of Alzheimer's disease. This study shows in transgenic mouse models of early Alzheimer's disease that the amnesia is due to a defect in memory retrieval rather than in encoding. Importantly, the 'forgotten' memories can be rescued by direct activation of hippocampal dentate gyrus engram cells, and the amnesia correlates with a progressive reduction of dentate gyrus engram cell spine density. The authors suggest that selective rescue of dentate gyrus engram cells and their spine density may lead to new therapeutic strategies to recoup lost memories in early Alzheimer's disease. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions1. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role2. However, it has been uncertain whether the observed amnesia in the early stages of AD 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 AD, 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 used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent3,4,5, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus 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 the early stages of AD.