Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

Cognitive deficits in Down syndrome (DS) can originate from cortical over-inhibition, but whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of a DS mouse model, we found specific enhancement of dendritic inhibition and altered excitability of perisomatic inhibitory interneurons. These effects resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. Our results reveal potential circuit mechanisms underlying cognitive deficits of DS.