The long-term goal of this project is to use mouse models to assess the potential clinical application of various pharmacological agents to the therapy of the mental deficit associated with Down syndrome (DS). Ts65Dn mice are the prime animal model for mental retardation in DS. These mice are trisomic for a chromosomal segment homologous to a large portion of human Chromosome 21 and display significant learning deficits in specific behavioral tests. Presently, there are two major factors limiting their widespread use in pre-clinical therapeutic trials: 1) poorly characterized neurological phenotype, which limits the scope of any pharmacological study; 2) low fertility rate, which curbs large- scale production. This project will address these limitations and systematically evaluate the efficacy of a series of 8 pharmacological agents in preventing and/or reversing learning deficits and DS-like neurological signs expressed by Ts65Dn mice. Each agent belongs to a different class of compounds for which there is a reasonable consensus about possible mechanisms of action in the central nervous system (CNS). Therefore, the investigation of their effect on Ts65Dn mice will be also a test for specific hypotheses about the pathophysiology of DS. To accomplish these goals, I propose 3 specific aims: 1) Evaluate the efficacy of 8 candidate therapeutic agents in preventing and/or reversing the learning deficit and DS-like neurological signs expressed by Ts65Dn mice; 2) Further investigate the neurological phenotype of Ts65Dn mice; 3) Use of in vitro fertilization techniques to test 4 key genetic issues related to Ts65Dn mice and to increase their availability.