1. Neuroscience
Download icon

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
Research Article
  • Cited 2
  • Views 1,348
  • Annotations
Cite this article as: eLife 2020;9:e58731 doi: 10.7554/eLife.58731
Voice your concerns about research culture and research communication: Have your say in our 7th annual survey.

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.

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.

Reviewing Editor

  1. Sacha B Nelson, Brandeis University, United States

Publication 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.

Metrics

  • 1,348
    Page views
  • 236
    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)

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
    Eun Ju Shin et al.
    Research Article Updated

    Studies in rats, monkeys, and humans have found action-value signals in multiple regions of the brain. These findings suggest that action-value signals encoded in these brain structures bias choices toward higher expected rewards. However, previous estimates of action-value signals might have been inflated by serial correlations in neural activity and also by activity related to other decision variables. Here, we applied several statistical tests based on permutation and surrogate data to analyze neural activity recorded from the striatum, frontal cortex, and hippocampus. The results show that previously identified action-value signals in these brain areas cannot be entirely accounted for by concurrent serial correlations in neural activity and action value. We also found that neural activity related to action value is intermixed with signals related to other decision variables. Our findings provide strong evidence for broadly distributed neural signals related to action value throughout the brain.

    1. Neuroscience
    Gonçalo Lopes et al.
    Research Article Updated

    Real-time rendering of closed-loop visual environments is important for next-generation understanding of brain function and behaviour, but is often prohibitively difficult for non-experts to implement and is limited to few laboratories worldwide. We developed BonVision as an easy-to-use open-source software for the display of virtual or augmented reality, as well as standard visual stimuli. BonVision has been tested on humans and mice, and is capable of supporting new experimental designs in other animal models of vision. As the architecture is based on the open-source Bonsai graphical programming language, BonVision benefits from native integration with experimental hardware. BonVision therefore enables easy implementation of closed-loop experiments, including real-time interaction with deep neural networks, and communication with behavioural and physiological measurement and manipulation devices.