microRNA-138 controls hippocampal interneuron function and short-term memory in mice

Abstract

The proper development and function of neuronal circuits relies on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause neurodevelopmental disorders, e.g. schizophrenia. microRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify miR138-5p as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated miR138-5p inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioural phenotypes associated with miR138-5p inactivation are paralleled by an upregulation of the schizophrenia-associated Erbb4, which we validated as a direct miR138-5p target gene. Our findings suggest that miR138-5p is a critical regulator of PV interneuron function in mice, with implications for cognition and schizophrenia. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.

Data availability

RNA-seq data has been deposited to GEO (accession no. GSE173982

The following data sets were generated

Article and author information

Author details

  1. Reetu Daswani

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Carlotta Gilardi

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Michael Soutschek

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8472-8124
  4. Pakruti Nanda

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Kerstin Weiss

    Institute for Physiological Chemistry, Philipp University of Marburg, Marberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Silvia Bicker

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6276-5653
  7. Roberto Fiore

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  8. Christoph Dieterich

    Department of Internal Medicine III, Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9468-6311
  9. Pierre-Luc Germain

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3418-4218
  10. Jochen Winterer

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    For correspondence
    jochen.winterer@hest.ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6800-6594
  11. Gerhard Schratt

    Department of Health Science and Technology, ETH Zurich, Zurich, Switzerland
    For correspondence
    gerhard.schratt@hest.ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7527-2025

Funding

Deutsche Forschungsgemeinschaft (SCHR 1136/4-2)

  • Gerhard Schratt

Eidgenössische Technische Hochschule Zürich (24 18-2 (NeuroSno))

  • Gerhard Schratt

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

Reviewing Editor

  1. John R Huguenard, Stanford University School of Medicine, United States

Ethics

Animal experimentation: All procedures were conducted in strict accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals and the relevant local or national rules and regulations of Switzerland and were subject to prior authorization by the local cantonal authorities (ZH017/2018, ZH196/17).

Version history

  1. Preprint posted: May 13, 2021 (view preprint)
  2. Received: September 20, 2021
  3. Accepted: March 13, 2022
  4. Accepted Manuscript published: March 15, 2022 (version 1)
  5. Version of Record published: March 29, 2022 (version 2)

Copyright

© 2022, Daswani 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. Reetu Daswani
  2. Carlotta Gilardi
  3. Michael Soutschek
  4. Pakruti Nanda
  5. Kerstin Weiss
  6. Silvia Bicker
  7. Roberto Fiore
  8. Christoph Dieterich
  9. Pierre-Luc Germain
  10. Jochen Winterer
  11. Gerhard Schratt
(2022)
microRNA-138 controls hippocampal interneuron function and short-term memory in mice
eLife 11:e74056.
https://doi.org/10.7554/eLife.74056

Share this article

https://doi.org/10.7554/eLife.74056

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