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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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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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  • 23 March 2016

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


  1. 1.

    Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001)

  2. 2.

    Alzheimer’s disease is a synaptic failure. Science 298, 789–791 (2002)

  3. 3.

    et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 103, 5161–5166 (2006)

  4. 4.

    et al. Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc. Natl Acad. Sci. USA 96, 3228–3233 (1999)

  5. 5.

    et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000)

  6. 6.

    et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572–580 (1991)

  7. 7.

    & Associative encoding and retrieval in Alzheimer’s and Huntington’s disease. Brain Cogn. 7, 335–347 (1988)

  8. 8.

    , & Differential impairment of semantic and episodic memory in Alzheimer’s and Huntington’s diseases: a controlled prospective study. J. Neurol. Neurosurg. Psychiatry 53, 1089–1095 (1990)

  9. 9.

    , & The neuropsychological profile of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006171 (2012)

  10. 10.

    et al. Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Hum. Mol. Genet . 13, 159–170 (2004)

  11. 11.

    et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–385 (2012)

  12. 12.

    et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013)

  13. 13.

    et al. Bidirectional switch of the valence associated with a hippocampal contextual memory engram. Nature 513, 426–430 (2014)

  14. 14.

    , , , & Engram cells retain memory under retrograde amnesia. Science 348, 1007–1013 (2015)

  15. 15.

    et al. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83, 189–201 (2014)

  16. 16.

    et al. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 68, 428–441 (2010)

  17. 17.

    , , & Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann. Neurol. 20, 472–481 (1986)

  18. 18.

    et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421 (2003)

  19. 19.

    et al. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer’s disease. PLoS One 3, e2935 (2008)

  20. 20.

    , , & Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys. J. 96, 1803–1814 (2009)

  21. 21.

    , & Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999)

  22. 22.

    & Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999)

  23. 23.

    et al. Engineering a memory with LTD and LTP. Nature 511, 348–352 (2014)

  24. 24.

    & Projection of the entorhinal layer II neurons in the rat as revealed by intracellular pressure-injection of neurobiotin. Hippocampus 3, 471–480 (1993)

  25. 25.

    et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013)

  26. 26.

    , , & Memory engram cells have come of age. Neuron 87, 918–931 (2015)

  27. 27.

    et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47–52 (2011)

  28. 28.

    , , & Localization of a stable neural correlate of associative memory. Science 317, 1230–1233 (2007)

  29. 29.

    et al. Exploring the sequence space for tetracycline-dependent transcriptional activators: novel mutations yield expanded range and sensitivity. Proc. Natl Acad. Sci. USA 97, 7963–7968 (2000)

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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


  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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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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