Estudio del efecto de la administración crónica de fármacos agonistas inversos selectivos para la subunidad a5 del receptor GABAa sobre los déficits cognitivos, electrofisiológicos y neuromorfológicos del ratón Ts65Dn, un modelo murino de síndrome de Down

Abstract

Down syndrome (DS) is associated with neurological alterations that lead to impairments in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. In this study, we show that chronic treatment to these mice with a selective GABAA a5 inverse agonist rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, adult neurogenesis and cell survival. We also show that this drug normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, the treatment supressed the hyperactivity observed in TS mice without inducing anxiety or convulsions or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition can reverse the functional and neuromorphological deficits of TS mice and support the potential therapeutic use of selective GABAA a5 inverse agonist to treat cognitive dysfunction in DS.