Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits

Abstract

The assembly of specific neuronal circuits relies on the expression of complementary molecular programs in presynaptic and postsynaptic neurons. In the cerebral cortex, the tyrosine kinase receptor ErbB4 is critical for the wiring of specific populations of GABAergic interneurons, in which it paradoxically regulates both the formation of inhibitory synapses as well as the development of excitatory synapses received by these cells. Here we found that Nrg1 and Nrg3, two members of the neuregulin family of trophic factors, respectively regulate the inhibitory outputs and excitatory inputs of interneurons in the mouse cerebral cortex. The differential role of Nrg1 and Nrg3 in this process is not due to their receptor-binding EGF-like domain, but rather to their distinctive subcellular localization within pyramidal cells. Our study reveals a novel strategy for the assembly of cortical circuits that involves the differential subcellular sorting of family-related synaptic proteins.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for the figures and figure supplements.

Article and author information

Author details

  1. David Exposito-Alonso

    Developmental Neurobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4950-2744
  2. Catarina Osório

    Department of Neuroscience, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5228-0599
  3. Clémence Bernard

    Developmental Neurobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Sandra Pascual-García

    Developmental Neurobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0536-1185
  5. Isabel del Pino

    Developmental Neurobiology, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Oscar Marín

    Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
    For correspondence
    oscar.marin@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6264-7027
  7. Beatriz Rico

    Developmental Neurobiology, King's College London, London, United Kingdom
    For correspondence
    beatriz.rico@kcl.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0581-851X

Funding

Medical Research Council (MR/S010785/1)

  • Oscar Marín
  • Beatriz Rico

Innovative Medicines Initiative (AIMS-2-TRIALS,777394)

  • Oscar Marín
  • Beatriz Rico

Fondation Roger de Spoelberch

  • Oscar Marín

La caixa Foundation

  • David Exposito-Alonso

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

Reviewing Editor

  1. Nils Brose, Max Planck Institute of Experimental Medicine, Germany

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals in accordance with European regulations, and Home Office personal and project licenses (PPL 0808-2004-2019, PPL PD025E9BC-2019-2024) under the UK Animals (Scientific Procedures) 1986 Act. The experiments performed in this study, have been designed to follow the 3R's rules whenever possible.

Version history

  1. Received: March 17, 2020
  2. Accepted: December 14, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)
  4. Version of Record published: December 22, 2020 (version 2)

Copyright

© 2020, Exposito-Alonso 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. David Exposito-Alonso
  2. Catarina Osório
  3. Clémence Bernard
  4. Sandra Pascual-García
  5. Isabel del Pino
  6. Oscar Marín
  7. Beatriz Rico
(2020)
Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits
eLife 9:e57000.
https://doi.org/10.7554/eLife.57000

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https://doi.org/10.7554/eLife.57000

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