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

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.

No sample-size calculation was performed. All data were subject to statistical tests to decide whether parametric or nonparametric tests should be applied. Sample sizes were chosen depending on the type of experiment and the difficulty of obtaining good-quality recordings. Sample sizes were comparable to other published studies using similar approaches.
No data passing a quality control was excluded from the analysis. Recorded neurons were excluded from the analysis when series resistance exceeded 30 MOhm. No data was excluded from the analysis a posteriori.
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