Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome.

Marie-Claude Potier,Jérémy Peixoto,Angela Michela De Stasi,Andrea Aguirre,Vikash Choudhary,Joana Lourenço,Javier Zorrilla De San Martin,Alberto Bacci,Cristina Donato

doi:10.7554/elife.58731

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.

Highlights

Down syndrome (DS) is a condition caused by full or partial trisomy of human chromosome 21, characterized by various physical and neurological features including mild to severe intellectual disability (Antonarakis et al, 2020)
Cognitive and synaptic plasticity deficits in Ts mice can be successfully treated by systemic application of a selective negative allosteric modulator of a5-containing GABAARs, a5IA (Braudeau et al, 2011; Duchon et al, 2020; Martınez-Cueet al., 2013; Schulz et al, 2019). a5-GABAARs are expressed at pyramidal neurons (PNs) synapses originating from dendrite-targeting interneurons: Martinotti cells (MCs) in the neocortex (Ali and Thomson, 2008) and O-LM in the hippocampus (Schulz et al, 2018)
We tested whether dendritic inhibition of PNs by MCs are affected in Ts mice

Summary

Introduction

Down syndrome (DS) is a condition caused by full or partial trisomy of human chromosome 21, characterized by various physical and neurological features including mild to severe intellectual disability (Antonarakis et al, 2020). Martinotti cells (MCs) are somatostatin (SST)-positive interneurons that inhibit distal dendrites of PNs, thereby controlling the integration of distal dendritic glutamatergic synaptic inputs originating from different regions of the brain (Tremblay et al, 2016). PV interneurons and MCs represent two major cortical inhibitory circuits, characterized by a precise division of labor during cortical activity Both forms of inhibition were shown to be involved in the entrainment of network oscillations (Cardin et al, 2009; Chen et al, 2017; Sohal et al, 2009; Veit et al, 2017) and in the cognitive performance during medial (m)PFC-dependent tasks (Abbas et al, 2018; Cho et al, 2015; Cummings and Clem, 2020). These results confirm over-inhibition in DS, and reveal unexpected functional alterations of specific GABAergic circuits in this condition

Results

Discussion

Materials and methods

Funding Funder Fondation Jerome Lejeune