Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome
- ICM - Institut du Cerveau, France
- University of Luxembourg, France
- Institut Pasteur, France
- ICM - Institut du Cerveau et de la Moelle épinière, France
- 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
Javier Zorrilla de San Martin
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
- 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
- Received: May 9, 2020
- Accepted: August 11, 2020
- Accepted Manuscript published: August 12, 2020 (version 1)
- 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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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
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