Inhibition of memory by a microRNA negative feedback loop that downregulates SNARE-mediated vesicle transport

  1. Rebecca S Mathew
  2. Antonis Tatarakis
  3. Andrii Rudenko
  4. Erin M Johnson-Venkatesh
  5. Yawei J Yang
  6. Elisabeth A Murphy
  7. Travis P Todd
  8. Scott P Schepers
  9. Nertila Siuti
  10. Anthony J Martorell
  11. William A Falls
  12. Sayamwong E Hammack
  13. Christopher A Walsh
  14. Li-Huei Tsai
  15. Hisashi Umemori
  16. Mark E Bouton
  17. Danesh Moazed  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard Medical School, United States
  2. The City College of the City University of New York, United States
  3. Harvard Medical School, United States
  4. Howard Hughes Medical Institute, Boston Children's Hospital, United States
  5. University of Vermont, United States
  6. Massachusetts Institute of Technology, United States

Abstract

The SNARE-mediated vesicular transport pathway plays major roles in synaptic remodeling associated with formation of long-term memories, but the mechanisms that regulate this pathway during memory acquisition are not fully understood. Here we identify miRNAs that are up-regulated in the rodent hippocampus upon contextual fear-conditioning and identify the vesicular transport and synaptogenesis pathways as the major targets of the fear-induced miRNAs. We demonstrate that miR-153, a member of this group, inhibits the expression of key components of the vesicular transport machinery, and down-regulates Glutamate receptor A1 trafficking and neurotransmitter release. MiR-153 expression is specifically induced during LTP induction in hippocampal slices and its knockdown in the hippocampus of adult mice results in enhanced fear memory. Our results suggest that miR-153, and possibly other fear-induced miRNAs, act as components of a negative feedback loop that blocks neuronal hyperactivity at least partly through the inhibition of the vesicular transport pathway.

Article and author information

Author details

  1. Rebecca S Mathew

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Antonis Tatarakis

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Andrii Rudenko

    Department of Biology, The City College of the City University of New York, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Erin M Johnson-Venkatesh

    Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yawei J Yang

    Division of Genetics, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Elisabeth A Murphy

    Division of Genetics, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Travis P Todd

    Department of Psychology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Scott P Schepers

    Department of Psychology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8051-7541
  9. Nertila Siuti

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Anthony J Martorell

    The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. William A Falls

    Department of Psychology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Sayamwong E Hammack

    Department of Psychology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Christopher A Walsh

    Division of Genetics, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Li-Huei Tsai

    The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Hisashi Umemori

    Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7198-2062
  16. Mark E Bouton

    Department of Psychology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Danesh Moazed

    Department of Cell Biology, Howard Hughes Medical Institute, Harvard Medical School, Boston, United States
    For correspondence
    danesh@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0321-6221

Funding

Howard Hughes Medical Institute

  • Danesh Moazed

Howard Hughes Medical Institute

  • Christopher A Walsh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gary L Westbrook, Vollum Institute, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Harvard Medical School. The protocol was approved by the Committee on the Ethics of Animal Experiments of Harvard Medical School. All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Version history

  1. Received: October 26, 2016
  2. Accepted: December 20, 2016
  3. Accepted Manuscript published: December 21, 2016 (version 1)
  4. Accepted Manuscript updated: December 24, 2016 (version 2)
  5. Version of Record published: February 6, 2017 (version 3)

Copyright

© 2016, Mathew et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rebecca S Mathew
  2. Antonis Tatarakis
  3. Andrii Rudenko
  4. Erin M Johnson-Venkatesh
  5. Yawei J Yang
  6. Elisabeth A Murphy
  7. Travis P Todd
  8. Scott P Schepers
  9. Nertila Siuti
  10. Anthony J Martorell
  11. William A Falls
  12. Sayamwong E Hammack
  13. Christopher A Walsh
  14. Li-Huei Tsai
  15. Hisashi Umemori
  16. Mark E Bouton
  17. Danesh Moazed
(2016)
Inhibition of memory by a microRNA negative feedback loop that downregulates SNARE-mediated vesicle transport
eLife 5:e22467.
https://doi.org/10.7554/eLife.22467

Share this article

https://doi.org/10.7554/eLife.22467

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