Combined Treatment With Environmental Enrichment and (-)-Epigallocatechin-3-Gallate Ameliorates Learning Deficits and Hippocampal Alterations in a Mouse Model of Down Syndrome

Intellectual disability in Down syndrome (DS) is accompanied by altered neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory. Recently, we have demonstrated beneficial effects of a combined treatment with green tea extract containing (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation in young adult DS individuals. Although we could reproduce the cognitive-enhancing effects in mouse models, the underlying mechanisms of these beneficial effects are unknown. Here, we explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in the Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved corticohippocampal-dependent learning and memory. Cognitive improvements were accompanied by a rescue of cornu ammonis 1 (CA1) dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and dentate gyrus.This research was supported by DIUE of Generalitat de Catalunya (Grups consolidats SGR 2014/1125); Fondation Jérôme Lejeune (Paris, France); Spanish Ministry of Economy and Finance (MINECO) grants SAF2013-49129-C2-1-R, BFU2011-28575, and MTM2015-64465-C2-1-R CDTI (“Smartfoods”); the CIBER of Rare Diseases (ISCIII initiative); and EU-Era Net Neuron PCIN-2013-060. The CRG has received support as a Severo Ochoa Center of Excellence SEV- 2012-O208. S.C.-S. received a FPI doctoral Fellowship from the MINECO (SAF2010-16427)