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.
Keywords: down syndrome; gamma oscillations; interneuron; mouse; neuroscience; prefrontal cortex; synaptic transmission; ts65dn.
Down syndrome is a genetic disorder caused by the presence of a third copy of chromosome 21. Affected individuals show delayed growth, characteristic facial features, altered brain development; with mild to severe intellectual disability. The exact mechanisms underlying the intellectual disability in Down syndrome are unclear, although studies in mice have provided clues. Drugs that reduce the inhibitory activity in the brain improve cognition in a mouse model of Down syndrome. This suggests that excessive inhibitory activity may contribute to the cognitive impairments. Many different neural circuits generate inhibitory activity in the brain. These circuits contain cells called interneurons. Sub-types of interneurons act via different mechanisms to reduce the activity of neurons. Identifying the interneurons that are affected in Down syndrome would thus improve our understanding of the brain basis of the disorder. Zorrilla de San Martin et al. compared mice with Down syndrome to unaffected control mice. The results revealed an increased activity in two types of inhibitory brain circuits in Down syndrome. The first contains interneurons called Martinotti cells. These help the brain to combine inputs from different sources. The second contains interneurons called parvalbumin-positive basket cells. These help different areas of the brain to synchronize their activity, which in turn makes it easier for those areas to exchange information. By mapping the changes in inhibitory circuits in Down syndrome, Zorrilla de San Martin et al. have provided new insights into the biological basis of the disorder. Future studies should examine whether targeting specific circuits with pharmacological treatments could ultimately help reduce the associated impairments.
© 2020, Zorrilla de San Martin et al.