1. Neuroscience
Download icon

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

Research Article
  • Cited 0
  • Views 60
  • Annotations
Cite this article as: eLife 2020;9:e57000 doi: 10.7554/eLife.57000

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.

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.

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.

Reviewing Editor

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

Publication history

  1. Received: March 17, 2020
  2. Accepted: December 14, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)

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.

Metrics

  • 60
    Page views
  • 8
    Downloads
  • 0
    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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    Tenzin Ngodup et al.
    Research Article Updated

    Auditory processing depends upon inhibitory signaling by interneurons, even at its earliest stages in the ventral cochlear nucleus (VCN). Remarkably, to date only a single subtype of inhibitory neuron has been documented in the VCN, a projection neuron termed the D-stellate cell. With the use of a transgenic mouse line, optical clearing, and imaging techniques, combined with electrophysiological tools, we revealed a population of glycinergic cells in the VCN distinct from the D-stellate cell. These multipolar glycinergic cells were smaller in soma size and dendritic area, but over ten-fold more numerous than D-stellate cells. They were activated by auditory nerve and T-stellate cells, and made local inhibitory synaptic contacts on principal cells of the VCN. Given their abundance, combined with their narrow dendritic fields and axonal projections, it is likely that these neurons, here termed L-stellate cells, play a significant role in frequency-specific processing of acoustic signals.

    1. Neuroscience
    Helen Wong et al.
    Research Article

    AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.