Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

  1. Javier Zorrilla de San Martin  Is a corresponding author
  2. Cristina Donato
  3. Jérémy Peixoto
  4. Andrea Aguirre
  5. Vikash Choudhary
  6. Angela Michela De Stasi
  7. Joana Lourenço
  8. Marie-Claude Potier  Is a corresponding author
  9. Alberto Bacci  Is a corresponding author
  1. ICM - Institut du Cerveau, France
  2. University of Luxembourg, France
  3. Institut Pasteur, France
  4. ICM - Institut du Cerveau et de la Moelle épinière, France
  5. Institut du Cerveau et de la Moelle épinière, ICM, France

Abstract

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

Data availability

Source data files have been provided for: Figure 1, Figure 1 - figure supplement 2, Figure 1 - figure supplement 3, Figure 2, Figure 2 figure supplement 1, Figure 2 figure supplement 2, Figure 3, Figure 3 - figure supplement 1, Figure 4, Figure 4 - figure supplement 1 and Figure 5

Article and author information

Author details

  1. Javier Zorrilla de San Martin

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau, Paris, France
    For correspondence
    javier.zorrilla@icm-institute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2848-7482
  2. Cristina Donato

    Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Jérémy Peixoto

    Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrea Aguirre

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau et de la Moelle épinière, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Vikash Choudhary

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Angela Michela De Stasi

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau et de la Moelle épinière, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Joana Lourenço

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau et de la Moelle épinière, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5550-9291
  8. Marie-Claude Potier

    Inserm U1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMRS 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France
    For correspondence
    marie-claude.potier@upmc.fr
    Competing interests
    The authors declare that no competing interests exist.
  9. Alberto Bacci

    CNRS UMR 7225 - Inserm U1127 - Sorbonne Université, ICM - Institut du Cerveau et de la Moelle épinière, Paris, France
    For correspondence
    alberto.bacci@icm-institute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3355-5892

Funding

Fondation Lejeune (#1790)

  • Javier Zorrilla de San Martin

Agence Nationale de la Recherche - ANR (ANR-12-EMMA-0010)

  • Marie-Claude Potier

Agence Nationale de la Recherche - ANR (ANR-16-CE16-0007-02)

  • Marie-Claude Potier

ICM - Institut du Cerveau (BBT-MOCONET)

  • Marie-Claude Potier
  • Alberto Bacci

Fondation Recherche Medicale - Equipe FRM (DEQ20150331684)

  • Alberto Bacci

NARSAD independent investigator grant

  • Alberto Bacci

Fondation Recherche Medicale - Equipe FRM (EQU201903007860)

  • Alberto Bacci

Agence Nationale de la Recherche - ANR (ANR-13-BSV4-0015-01)

  • Alberto Bacci

Agence Nationale de la Recherche - ANR (ANR-17-CE16-0026-01)

  • Alberto Bacci

Agence Nationale de la Recherche - ANR (ANR-18-CE16-0001-01)

  • Alberto Bacci

Agence Nationale de la Recherche - ANR (ANR-10-IAIHU-06)

  • Marie-Claude Potier
  • Alberto Bacci

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

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Ethics

Animal experimentation: Animal experimentation: Experimental procedures followed National and European guidelines, and have been approved by the authors' institutional review boards (French Ministry of Research and Innovation (APAFIS#2599-2015110414316981v21). Every effort was made to minimize suffering.

Version history

  1. Received: May 9, 2020
  2. Accepted: August 11, 2020
  3. Accepted Manuscript published: August 12, 2020 (version 1)
  4. Version of Record published: September 9, 2020 (version 2)

Copyright

© 2020, Zorrilla de San Martin 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. Javier Zorrilla de San Martin
  2. Cristina Donato
  3. Jérémy Peixoto
  4. Andrea Aguirre
  5. Vikash Choudhary
  6. Angela Michela De Stasi
  7. Joana Lourenço
  8. Marie-Claude Potier
  9. Alberto Bacci
(2020)
Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome
eLife 9:e58731.
https://doi.org/10.7554/eLife.58731

Share this article

https://doi.org/10.7554/eLife.58731

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