A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory

  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 T 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 T 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.

Metrics

  • 2,913
    views
  • 737
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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 T 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)
A microRNA negative feedback loop downregulates vesicle transport and inhibits fear memory
eLife 5:e22467.
https://doi.org/10.7554/eLife.22467

Share this article

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

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Kevin Portmann, Aline Linder, Klaus Eyer
    Research Article

    Cytokine polyfunctionality is a well-established concept in immune cells, especially T cells, and their ability to concurrently produce multiple cytokines has been associated with better immunological disease control and subsequent effectiveness during infection and disease. To date, only little is known about the secretion dynamics of those cells, masked by the widespread deployment of mainly time-integrated endpoint measurement techniques that do not easily differentiate between concurrent and sequential secretion. Here, we employed a single-cell microfluidic platform capable of resolving the secretion dynamics of individual PBMCs. To study the dynamics of poly-cytokine secretion, as well as the dynamics of concurrent and sequential polyfunctionality, we analyzed the response at different time points after ex vivo activation. First, we observed the simultaneous secretion of cytokines over the measurement time for most stimulants in a subpopulation of cells only. Second, polyfunctionality generally decreased with prolonged stimulation times and revealed no correlation with the concentration of secreted cytokines in response to stimulation. However, we observed a general trend towards higher cytokine secretion in polyfunctional cells, with their secretion dynamics being distinctly different from mono-cytokine-secreting cells. This study provided insights into the distinct secretion behavior of heterogenous cell populations after stimulation with well-described agents and such a system could provide a better understanding of various immune dynamics in therapy and disease.

    1. Cell Biology
    2. Neuroscience
    Toshiharu Ichinose, Shu Kondo ... Hiromu Tanimoto
    Research Article

    Multicellular organisms are composed of specialized cell types with distinct proteomes. While recent advances in single-cell transcriptome analyses have revealed differential expression of mRNAs, cellular diversity in translational profiles remains underinvestigated. By performing RNA-seq and Ribo-seq in genetically defined cells in the Drosophila brain, we here revealed substantial post-transcriptional regulations that augment the cell-type distinctions at the level of protein expression. Specifically, we found that translational efficiency of proteins fundamental to neuronal functions, such as ion channels and neurotransmitter receptors, was maintained low in glia, leading to their preferential translation in neurons. Notably, distribution of ribosome footprints on these mRNAs exhibited a remarkable bias toward the 5′ leaders in glia. Using transgenic reporter strains, we provide evidence that the small upstream open-reading frames in the 5’ leader confer selective translational suppression in glia. Overall, these findings underscore the profound impact of translational regulation in shaping the proteomics for cell-type distinction and provide new insights into the molecular mechanisms driving cell-type diversity.