1. Chromosomes and Gene Expression
  2. Neuroscience

Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory

  1. Claire C Chen
  2. Joseph Han
  3. Carlene A Chinn
  4. Jacob S Rounds
  5. Xiang Li
  6. Mehran Nikan
  7. Marie Myszka
  8. Liqi Tong
  9. Luiz F M Passalacqua
  10. Timothy Bredy
  11. Marcelo A Wood  Is a corresponding author
  12. Andrej Luptak  Is a corresponding author
  1. University of California, Irvine, United States
  2. University of Queensland, Australia
  3. Ionis Pharmaceuticals, United States
https://doi.org/10.7554/eLife.90116
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Cite this article
  1. Claire C Chen
  2. Joseph Han
  3. Carlene A Chinn
  4. Jacob S Rounds
  5. Xiang Li
  6. Mehran Nikan
  7. Marie Myszka
  8. Liqi Tong
  9. Luiz F M Passalacqua
  10. Timothy Bredy
  11. Marcelo A Wood
  12. Andrej Luptak
(2024)
Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory
eLife 13:e90116.
https://doi.org/10.7554/eLife.90116
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Abstract

A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element binding protein 3 (Cpeb3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozyme’s self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the Cpeb3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 - 7.

Article and author information

Author details

  1. Claire C Chen

    Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  2. Joseph Han

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  3. Carlene A Chinn

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  4. Jacob S Rounds

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  5. Xiang Li

    Queensland Brain Institute, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.

  6. Mehran Nikan

    Ionis Pharmaceuticals, Carlsbad, United States
    Competing interests
    Mehran Nikan, Mehran Nikan is affiliated with Ionis Pharmaceuticals. The author has no financial interests to declare..

  7. Marie Myszka

    Department of Chemistry, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  8. Liqi Tong

    Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.

  9. Luiz F M Passalacqua

    Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5490-2427

  10. Timothy Bredy

    Queensland Brain Institute, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3280-126X

  11. Marcelo A Wood

    Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States
    For correspondence
    mwood@uci.edu
    Competing interests
    No competing interests declared.

  12. Andrej Luptak

    Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, United States
    For correspondence
    aluptak@uci.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0632-5442

Funding

National Institutes of Health (R01AG051807)

  • Marcelo A Wood

National Institutes of Health (RF1AG057558)

  • Marcelo A Wood

National Science Foundation (1804220)

  • Andrej Luptak

National Science Foundation (1330606)

  • Andrej Luptak

National Science Foundation Graduate Research Fellowship Program

  • Claire C Chen

National Institutes of Health (R01CA229696)

  • Claire C Chen

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

Reviewing Editor

  1. Anne E West, Duke University, United States

Ethics

Animal experimentation: All experimental procedures were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of the University of California, Irvine.

Version history

  1. Preprint posted: June 9, 2023 (view preprint)
  2. Received: June 13, 2023
  3. Accepted: February 5, 2024
  4. Accepted Manuscript published: February 6, 2024 (version 1)
  5. Version of Record published: March 7, 2024 (version 2)

Copyright

© 2024, Chen 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. Claire C Chen
  2. Joseph Han
  3. Carlene A Chinn
  4. Jacob S Rounds
  5. Xiang Li
  6. Mehran Nikan
  7. Marie Myszka
  8. Liqi Tong
  9. Luiz F M Passalacqua
  10. Timothy Bredy
  11. Marcelo A Wood
  12. Andrej Luptak
(2024)
Inhibition of Cpeb3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory
eLife 13:e90116.
https://doi.org/10.7554/eLife.90116

Share this article

https://doi.org/10.7554/eLife.90116

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