Neurotrophic treatment to rescue synaptic plasticity and cognitive functions in a mouse model of Down Syndrome

Down syndrome (DS) is the most frequent cause of mental retardation in children and adults. Previous studies have demonstrated that trisomic DS mouse models reproduce essential genetic and cognitive deficits of the human syndrome. In particular, learning and memory deficits characteristic of the disease are mainly determined by impaired synaptic communication (the way information travels from one neuron to another) and decreased adult neurogenesis (i.e., the generation of new neurons) in the hippocampus, a brain region with a pivotal role in cognition. The occurrence of such defects is likely underlying the cognitive impairment associated with DS in different ways. Indeed, synaptic deficits modify optimal neuronal communication, whereas reduced neurogenesis decreases the number of communicating units. Moreover, DS patients have also a high chance of undergoing a progressive neuronal loss with aging, similar to Alzheimer disease. Therefore, we propose to test on a DS mouse model (Ts65Dn mice) an innovative pharmacological strategy concurrently targeting these three different aspects of the disease. Our approach consists in the use of a single drug able to stimulate cellular signaling events that promote synaptic communication, adult neurogenesis and attenuate neuronal injury. We expect that this treatment will rescue learning and memory of Ts65Dn mice by correcting all of these defects. Thus, our experiments will test in a reliable animal model a novel and safe therapeutic approach with a good potential to be translated into clinical therapy to ameliorate conditions of DS in human patients.