Cognitive enhancement by pharmacological and behavioral interventions: the murine Down syndrome model

Abstract

The cognitive deficits in Down syndrome (DS) are attributed to an excessive hippocampal inhibition, which obstructs neuronal plasticity and normal learning and memory, a view which is largely based on studies of Ts65Dn mice, the best characterized mouse model of DS. The cognitive behavioral deficits of Ts65Dn mice can be rescued by reducing GABAergic inhibition, most selectively by partial inverse agonists acting on α5 GABA-A receptors, of which one compound has recently entered clinical trials in DS. Most remarkably, the improved cognitive performance of Ts65Dn can persist for weeks and months after cessation of drug treatment, as demonstrated for the non-specific GABA antagonist pentylenetetrazole. The Alzheimer drugs, memantine and donepezil largely fail to show any benefit. Finally, repeated non-invasive sensory stimulation such as over-training or enriching the environment, are able to enhance the learning performance which underlines the reversibility of an obstructed neuronal plasticity in Ts65Dn mice.