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.
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.
Metrics
-
- 2,540
- views
-
- 431
- downloads
-
- 29
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
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)
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
Further reading
-
- Neuroscience
Locomotion is controlled by spinal circuits that interact with supraspinal drives and sensory feedback from the limbs. These sensorimotor interactions are disrupted following spinal cord injury. The thoracic lateral hemisection represents an experimental model of an incomplete spinal cord injury, where connections between the brain and spinal cord are abolished on one side of the cord. To investigate the effects of such an injury on the operation of the spinal locomotor network, we used our computational model of cat locomotion recently published in eLife (Rybak et al., 2024) to investigate and predict changes in cycle and phase durations following a thoracic lateral hemisection during treadmill locomotion in tied-belt (equal left-right speeds) and split-belt (unequal left-right speeds) conditions. In our simulations, the ‘hemisection’ was always applied to the right side. Based on our model, we hypothesized that following hemisection the contralesional (‘intact’, left) side of the spinal network is mostly controlled by supraspinal drives, whereas the ipsilesional (‘hemisected’, right) side is mostly controlled by somatosensory feedback. We then compared the simulated results with those obtained during experiments in adult cats before and after a mid-thoracic lateral hemisection on the right side in the same locomotor conditions. Our experimental results confirmed many effects of hemisection on cat locomotion predicted by our simulations. We show that having the ipsilesional hindlimb step on the slow belt, but not the fast belt, during split-belt locomotion substantially reduces the effects of lateral hemisection. The model provides explanations for changes in temporal characteristics of hindlimb locomotion following hemisection based on altered interactions between spinal circuits, supraspinal drives, and somatosensory feedback.
-
- Neuroscience
Reversing opioid overdoses in rats using a drug that does not enter the brain prevents the sudden and severe withdrawal symptoms associated with therapeutics that target the central nervous system.
