Memory retrieval

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

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

• Affiliations
• Contributions
• Corresponding author

Nature

 

531,

 

508–512

 

(24 March 2016)

 

doi:10.1038/nature17172

Received

 

06 August 2015 

Accepted

 

28 January 2016 

Published online

 

16 March 2016

Corrected online

 

23 March 2016

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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-dependent^3, 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.