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

  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  Is a corresponding author
  11. Gerhard Schratt  Is a corresponding author
  1. ETH Zurich, Switzerland
  2. Philipp University of Marburg, Germany
  3. Heidelberg University, Germany

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.

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).

Reviewing Editor

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

Publication 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.

Metrics

  • 921
    Page views
  • 177
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. 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

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Hilary Scott, Boris Novikov ... Vladislav Panin
    Research Article

    Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.

    1. Neuroscience
    Alana Jaskir, Michael J Frank
    Research Article

    The basal ganglia (BG) contribute to reinforcement learning (RL) and decision making, but unlike artificial RL agents, it relies on complex circuitry and dynamic dopamine modulaton of opponent striatal pathways to do so. We develop the OpAL* model to assess the normative advantages of this circuitry. In OpAL*, learning induces opponent pathways to differentially emphasize the history of positive or negative outcomes for each action. Dynamic DA modulation then amplifies the pathway most tuned for the task environment. This efficient coding mechanism avoids a vexing explore-exploit tradeoff that plagues traditional RL models in sparse reward environments. OpAL* exhibits robust advantages over alternative models, particularly in environments with sparse reward and large action spaces. These advantages depend on opponent and nonlinear Hebbian plasticity mechanisms previously thought to be pathological. Finally, OpAL* captures risky choice patterns arising from DA and environmental manipulations across species, suggesting that they result from a normative biological mechanism.