BIDIRECTIONAL MODULATION OF PV AND SOM INTERNEURONS RESCUES LTP AND COGNITIVE IMPAIRMENT IN THE TS65DN MOUSE MODEL OF DOWN SYNDROME

A prominent hypothesis in Down Syndrome (DS) is that both synaptic and behavioural abnormalities arise from altered GABAergic signalling. Notably, deficits in synaptic plasticity—such as reduced long-term potentiation (LTP)—and memory impairments can be rescued by GABA_A-receptor antagonists or by restoring altered chloride levels in pyramidal neurons of DS mice. However, while GABAergic alterations in DS are well known from the perspective of excitatory neurons, such as pyramidal and granule cells, cell type–specific alterations within GABAergic interneurons remain poorly investigated.
Here, we characterized parvalbumin (PV) and somatostatin (SOM)-positive interneurons in the hippocampus of 3-months-old adults of the Ts65Dn mouse model of DS versus control littermates by immunohistochemistry and electrophysiology on acute brain slices. Ts65Dn mice showed fewer PV interneurons with reduced maximal action potential frequency in the stratum pyramidale and dentate gyrus of the hippocampus, indicating a less excitable phenotype. Ts65Dn SOM interneurons were increased in the CA1 region and showed higher action potential frequency, similarly to control PV neurons. Accordingly, Schaffer collateral–CA1 theta-burst stimulation (CA3–CA1 LTP) in Ts65Dn mice expressing either excitatory DREADDs in PV interneurons or inhibitory DREADDs in SOM interneurons in the presence of DREADD activator clozapine n-oxide (CNO) rescued synaptic plasticity and contextual fear memory to control levels, with no significant effect on control mice.
Altogether, our results suggest that PV and SOM interneurons are distinctly altered in Ts65Dn mice, and that their opposite modulation can rescue their impairment. These findings open to interneuron-specific manipulation as a promising therapeutic strategy in DS.