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.

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.

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.

Download links

Share this article

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

Further reading

    1. Neuroscience
    Gergely F Turi, Sasa Teng ... Yueqing Peng
    Research Article

    Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.

    1. Neuroscience
    Ulrike Pech, Jasper Janssens ... Patrik Verstreken
    Research Article

    The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence of nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to the emergence of motor issues, patients frequently experience non-motor symptoms, such as a reduced sense of smell (hyposmia). The cellular and molecular bases for these early defects remain enigmatic. To explore this, we developed a new collection of five fruit fly models of familial Parkinsonism and conducted single-cell RNA sequencing on young brains of these models. Interestingly, cholinergic projection neurons are the most vulnerable cells, and genes associated with presynaptic function are the most deregulated. Additional single nucleus sequencing of three specific brain regions of Parkinson’s disease patients confirms these findings. Indeed, the disturbances lead to early synaptic dysfunction, notably affecting cholinergic olfactory projection neurons crucial for olfactory function in flies. Correcting these defects specifically in olfactory cholinergic interneurons in flies or inducing cholinergic signaling in Parkinson mutant human induced dopaminergic neurons in vitro using nicotine, both rescue age-dependent dopaminergic neuron decline. Hence, our research uncovers that one of the earliest indicators of disease in five different models of familial Parkinsonism is synaptic dysfunction in higher-order cholinergic projection neurons and this contributes to the development of hyposmia. Furthermore, the shared pathways of synaptic failure in these cholinergic neurons ultimately contribute to dopaminergic dysfunction later in life.