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

Nature volume 531, pages 508512 (24 March 2016) | Download Citation

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Abstract

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.

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Change history

  • 23 March 2016

    The PDF was replaced to correct the presentation of Extended Data Figures 3 and 7.

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Acknowledgements

We thank X. Liu for the c-Fos-tTA construct; S. Huang, T. Okuyama and T. Kitamura for help with experiments; W. Yu, S. LeBlanc and X. Zhou for technical assistance; L. Brenner for proofreading; and all members of the Tonegawa laboratory for their support. We thank M. Luo for sharing the DTR coding sequence. This work was supported by the RIKEN Brain Science Institute, the Howard Hughes Medical Institute, and the JPB Foundation (to S.T.).

Author information

Affiliations

  1. RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Dheeraj S. Roy
    • , Autumn Arons
    • , Teryn I. Mitchell
    • , Michele Pignatelli
    • , Tomás J. Ryan
    •  & Susumu Tonegawa
  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Autumn Arons
    • , Tomás J. Ryan
    •  & Susumu Tonegawa

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Contributions

D.S.R. and S.T. contributed to the study design. D.S.R., A.A., T.I.M., M.P. and T.J.R. contributed to the data collection and interpretation. D.S.R. cloned all constructs. D.S.R. and A.A. conducted the surgeries, behaviour experiments and histological analyses. D.S.R. and S.T. wrote the paper. All authors discussed and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Susumu Tonegawa.

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https://doi.org/10.1038/nature17172

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