1. Neuroscience

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
https://doi.org/10.7554/eLife.58731
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

  • 2,140
    Page views
  • 365
    Downloads
  • 19
    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. 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

Categories and tags

Research organism

Further reading

    1. Neuroscience

    Cholinergic and noradrenergic axonal activity contains a behavioral-state signal that is coordinated across the dorsal cortex

    Lindsay Collins, John Francis ... David A McCormick
    Research Article Updated

    Fluctuations in brain and behavioral state are supported by broadly projecting neuromodulatory systems. In this study, we use mesoscale two-photon calcium imaging to examine spontaneous activity of cholinergic and noradrenergic axons in awake mice in order to determine the interaction between arousal/movement state transitions and neuromodulatory activity across the dorsal cortex at distances separated by up to 4 mm. We confirm that GCaMP6s activity within axonal projections of both basal forebrain cholinergic and locus coeruleus noradrenergic neurons track arousal, indexed as pupil diameter, and changes in behavioral engagement, as reflected by bouts of whisker movement and/or locomotion. The broad coordination in activity between even distant axonal segments indicates that both of these systems can communicate, in part, through a global signal, especially in relation to changes in behavioral state. In addition to this broadly coordinated activity, we also find evidence that a subpopulation of both cholinergic and noradrenergic axons may exhibit heterogeneity in activity that appears to be independent of our measures of behavioral state. By monitoring the activity of cholinergic interneurons in the cortex, we found that a subpopulation of these cells also exhibit state-dependent (arousal/movement) activity. These results demonstrate that cholinergic and noradrenergic systems provide a prominent and broadly synchronized signal related to behavioral state, and therefore may contribute to state-dependent cortical activity and excitability.

    1. Neuroscience

    Early language exposure affects neural mechanisms of semantic representations

    Xiaosha Wang, Bijun Wang, Yanchao Bi
    Research Article Updated

    One signature of the human brain is its ability to derive knowledge from language inputs, in addition to nonlinguistic sensory channels such as vision and touch. How does human language experience modulate the mechanism by which semantic knowledge is stored in the human brain? We investigated this question using a unique human model with varying amounts and qualities of early language exposure: early deaf adults who were born to hearing parents and had reduced early exposure and delayed acquisition of any natural human language (speech or sign), with early deaf adults who acquired sign language from birth as the control group that matches on nonlinguistic sensory experiences. Neural responses in a semantic judgment task with 90 written words that were familiar to both groups were measured using fMRI. The deaf group with reduced early language exposure, compared with the deaf control group, showed reduced semantic sensitivity, in both multivariate pattern (semantic structure encoding) and univariate (abstractness effect) analyses, in the left dorsal anterior temporal lobe (dATL). These results provide positive, causal evidence that language experience drives the neural semantic representation in the dATL, highlighting the roles of language in forming human neural semantic structures beyond nonverbal sensory experiences.

    1. Neuroscience

    Two conserved vocal central pattern generators broadly tuned for fast and slow rates generate species-specific vocalizations in Xenopus clawed frogs

    Ayako Yamaguchi, Manon Peltier
    Research Article Updated

    Across phyla, males often produce species-specific vocalizations to attract females. Although understanding the neural mechanisms underlying behavior has been challenging in vertebrates, we previously identified two anatomically distinct central pattern generators (CPGs) that drive the fast and slow clicks of male Xenopus laevis, using an ex vivo preparation that produces fictive vocalizations. Here, we extended this approach to four additional species, X. amieti, X. cliivi, X. petersii, and X. tropicalis, by developing ex vivo brain preparation from which fictive vocalizations are elicited in response to a chemical or electrical stimulus. We found that even though the courtship calls are species-specific, the CPGs used to generate clicks are conserved across species. The fast CPGs, which critically rely on reciprocal connections between the parabrachial nucleus and the nucleus ambiguus, are conserved among fast-click species, and slow CPGs are shared among slow-click species. In addition, our results suggest that testosterone plays a role in organizing fast CPGs in fast-click species, but not in slow-click species. Moreover, fast CPGs are not inherited by all species but monopolized by fast-click species. The results suggest that species-specific calls of the genus Xenopus have evolved by utilizing conserved slow and/or fast CPGs inherited by each species.