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 have explored the effects of a combined therapy with environmental enrichment (EE) and EGCG in Ts65Dn mouse model of DS at young age. Our results show that combined EE-EGCG treatment improved cortico-hippocampal dependent learning and memory. Cognitive improvements were accompanied by a rescue of CA1 dendritic spine density and a normalization of the proportion of excitatory and inhibitory synaptic markers in CA1 and DG.
Significance Statement: Therapeutic methods for improving intellectual disability in Down syndrome (DS) are limited and their outcome remains unsatisfactory. Recently, we demonstrated that combined treatment with (-)-epigallocatechin-3-gallate (EGCG) and cognitive stimulation rescued cognitive deficits in DS individuals in a phase II clinical trial and also in middle age Ts65Dn mouse model of DS. Here, we show that EE-EGCG treatment improves cortico-hippocampal dependent learning and memory deficits in young trisomic mice, restores CA1 hippocampal dendritic spine density and mitigates disruptions in excitatory/inhibitory synaptic puncta in CA1 and DG.
Our results suggest that therapies with the capacity to simultaneously target several abnormal processes underlying intellectual disability and to efficiently act favoring physiologic plasticity-enhancing interventions such as EE are optimal for disease-modifying interventions.
Authors report no conflict of interest.
MINECO | Consejo Superior de Investigaciones Científicas (CSIC) [SAF2013-49129-C2-1-R], DIUE of Generalitat de Catalunya (Grups consolidats) [SGR 2014/1125], Fondation Jérôme Lejeune, CDTI Smartfoods, CIBER of Rare Disease ISCIII initiave, EU-Era Net Neuron [PCIN-2013- 060], Severo Ochoa Center of Excellence [SEV- 2012-0208].