MicroRNA-218 instructs proper assembly of hippocampal networks

  1. Seth R Taylor  Is a corresponding author
  2. Mariko Kobayashi
  3. Antonietta Vilella
  4. Durgesh Tiwari
  5. Norjin Zolboot
  6. Jessica X Du
  7. Kathryn R Spencer
  8. Andrea Hartzell
  9. Carol Girgiss
  10. Yusuf T Abaci
  11. Yufeng Shao
  12. Claudia De Sanctis
  13. Gian Carlo Bellenchi
  14. Robert B Darnell
  15. Christina Gross
  16. Michele Zoli
  17. Darwin K Berg
  18. Giordano Lippi  Is a corresponding author
  1. Brigham Young University, United States
  2. Howard Hughes Medical Institute, Rockefeller University, United States
  3. University of Modena and Reggio Emilia, Italy
  4. Cincinnati Children's Hospital Medical Center, United States
  5. Scripps Research Institute, United States
  6. University of California, San Diego, United States
  7. Institute of Genetics and Biophysics A Buzzati-Traverso, Italy

Abstract

The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.

Data availability

RNA-seq data has been deposited to GEO (accession number GSE241245)

The following data sets were generated

Article and author information

Author details

  1. Seth R Taylor

    Division of Biological Sciences, Brigham Young University, Provo, United States
    For correspondence
    seth_taylor@byu.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Mariko Kobayashi

    Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Antonietta Vilella

    Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Durgesh Tiwari

    Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Norjin Zolboot

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jessica X Du

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kathryn R Spencer

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Andrea Hartzell

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Carol Girgiss

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Yusuf T Abaci

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Yufeng Shao

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Claudia De Sanctis

    Institute of Genetics and Biophysics A Buzzati-Traverso, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Gian Carlo Bellenchi

    Institute of Genetics and Biophysics A Buzzati-Traverso, Naples, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Robert B Darnell

    Laboratory of Molecular Neuro-oncology, Howard Hughes Medical Institute, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5134-8088
  15. Christina Gross

    Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6057-2527
  16. Michele Zoli

    Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  17. Darwin K Berg

    Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Giordano Lippi

    Department of Neuroscience, Scripps Research Institute, La Jolla, United States
    For correspondence
    glippi@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3911-0525

Funding

National Institutes of Health (1 S10 OD026817-01)

  • Giordano Lippi

Ministero dell'Istruzione, dell'Università e della Ricerca (1R01NS092705)

  • Michele Zoli

National Institutes of Health (2R01NS012601)

  • Darwin K Berg

National Institutes of Health (1R21NS087342)

  • Darwin K Berg

National Institutes of Health (1R01NS121223)

  • Giordano Lippi

National Institutes of Health (1R01NS092705)

  • Christina Gross

Tobacco-Related Disease Research Program (22XT-0016,21FT-0027)

  • Darwin K Berg

Whitehall Foundation (2018-12-55)

  • Giordano Lippi

Autism Speaks (12923)

  • Norjin Zolboot

American Epilepsy Society (12923)

  • Andrea Hartzell

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

Ethics

Animal experimentation: All experimental procedures at UCSD, CCHMH and SRI were performed as approved by the Institutional Animal Care and Use Committees and according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. Behavioral and in vivo experiments at UNIMORE were conducted in accordance with the European Community Council Directive (86/609/EEC) of November 24, 1986, and approved by the ethics committee (authorization number: 37/2018PR).

Copyright

© 2023, Taylor 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. Seth R Taylor
  2. Mariko Kobayashi
  3. Antonietta Vilella
  4. Durgesh Tiwari
  5. Norjin Zolboot
  6. Jessica X Du
  7. Kathryn R Spencer
  8. Andrea Hartzell
  9. Carol Girgiss
  10. Yusuf T Abaci
  11. Yufeng Shao
  12. Claudia De Sanctis
  13. Gian Carlo Bellenchi
  14. Robert B Darnell
  15. Christina Gross
  16. Michele Zoli
  17. Darwin K Berg
  18. Giordano Lippi
(2023)
MicroRNA-218 instructs proper assembly of hippocampal networks
eLife 12:e82729.
https://doi.org/10.7554/eLife.82729

Share this article

https://doi.org/10.7554/eLife.82729

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