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Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization

Nature Medicine volume 24, pages 438–449 (2018)Cite this article

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Abstract

Memories become less precise and generalized over time as memory traces reorganize in hippocampal–cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal–cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC–SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC–SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG–CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.

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Figure 1: ABLIM3 is a learning-regulated molecular brake of DGC–SLIN connectivity.
Figure 2: ABLIM3 downregulation in DGCs increases mEPSCs in PV+ SLINs and PV+ puncta in CA3.
Figure 3: ABLIM3 downregulation in DGCs enhances feedforward inhibition onto CA3.
Figure 4: Enhancing DGC recruitment of inhibition promotes engram maintenance and governs reactivation of remote memory traces in hippocampal–cortical and BLA networks.
Figure 5: ABLIM3 downregulation in DGCs decreases generalization of remote fear memories.
Figure 6: ABLIM3 downregulation in the DG of aged mice enhances DGC–PV+ SLIN connectivity and improves remote memory precision.

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Acknowledgements

We wish to thank members of the Sahay lab for comments on the manuscript and the late N.J. Sahay for advice. We are thankful to S. Tonegawa (MIT) for the AAV9-tetO-ChR2 construct, M.E. Greenberg (Harvard Medical School) for the lentiviral pLLX vector, J. Rajagopal (MGH) for the HEK293T cells and S. Ramirez (Boston University) for the AAV9-tetO-ChR2-mCherry virus. L.Z. is supported by US National Institutes of Health (NIH) grant R01MH104450. C.C. is an investigator of the Howard Hughes Medical Institute. A.S. acknowledges support from the NIH Biobehavioral Research Awards for Innovative New Scientists (BRAINS; grant R01MH104175), the NIH–National Institute on Aging (NIA) grant R01AG048908, NIH grant 1R01MH111729, the Ellison Medical Foundation New Scholar in Aging, the Whitehall Foundation, an Inscopix Decode award, a NARSAD Independent Investigator Award, Ellison Family Philanthropic support, the Blue Guitar Fund, a Harvard Neurodiscovery Center–MADRC Center Pilot Grant award, and a Harvard Stem Cell Institute Development grant and HSCI seed grant. C.H. was supported by a 2016 HSCI Harvard Internship Program Award.

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Authors and Affiliations

  1. Center for Regenerative Medicine, Massachusetts General Hospital (MGH), Boston, Massachusetts, USA

    Nannan Guo, Charlotte Herber, Michael TaeWoo Kim, Antoine Besnard, Paoyan Lin & Amar Sahay

  2. Harvard Stem Cell Institute, Cambridge, Massachusetts, USA

    Nannan Guo, Charlotte Herber, Michael TaeWoo Kim, Antoine Besnard, Paoyan Lin & Amar Sahay

  3. Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Nannan Guo, Michael TaeWoo Kim, Antoine Besnard, Paoyan Lin & Amar Sahay

  4. Department of Pharmacology, University of Washington, Seattle, Washington, USA

    Marta E Soden & Larry S Zweifel

  5. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA

    Marta E Soden & Larry S Zweifel

  6. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    Xiang Ma & Constance L Cepko

  7. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA

    Xiang Ma & Constance L Cepko

  8. BROAD Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts, USA

    Amar Sahay

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Contributions

N.G., M.E.S., C.H., M.T.K., P.L. and A.B. performed experiments; X.M. and C.L.C. contributed reagents; M.E.S. and L.S.Z. contributed to slice electrophysiology experiments and interpretation of the data; A.S. and N.G. co-developed the concept, analyzed data and wrote the manuscript; and A.S. conceived the project and supervised all aspects of the project.

Corresponding author

Correspondence to Amar Sahay.

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Competing interests

A.S. and N.G. are named co-inventors on a patent application (US 2016/0376588 A1, PCT/US 15/20540) relating to this study.

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Guo, N., Soden, M., Herber, C. et al. Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization. Nat Med 24, 438–449 (2018). https://doi.org/10.1038/nm.4491

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