The development of mouse models of Down Syndrome, with appropriate gene expression to mimic what takes place with a trisomy of human chromosome 21, provides test systems for potential therapeutic interventions aimed at improving cognitive performance. As detailed under Dr. Davisson's Project, the Ts65Dn mouse containing homologs to the majority of the genes on human chromosome 21. This segmental trisomy model has a number of distinct advantages over previous models, not the least of which is survival to adulthood. We and others have demonstrative a cognitive phenotype in the Ts65Dn mouse which has clear similarities to that seen in Down Syndrome. Ts65Dn mice demonstrate performance deficits in tests of learning and memory against a background of relatively intact motor and sensory abilities. Both acetylcholine and glutamate play important roles in learning and memory and are involved in neural organization during development. Alterations of cholinergic and glutamatergic activity in DS have been identified. The proposed experiments will 1) provide a more complete characterization of the development of cholinergic and glutamatergic systems in Ts65Dn mice. This characterization will provide a necessary background for proposed experiments aimed at, 2) assessing whether strategies aimed at blocking cholinergic degradation with the acetyl cholinesterase at, 2) assessing whether strategies aimed at blocking cholinergic degradation with the acetyl cholinesterase inhibitor donepezil or producing a development increase in cholinergic function with prenatal choline can improve performance in the Ts65Dn mouse, 3) assessing whether developmental treatment with piracetan alone, or piracetam combined with prenatal choline administration, improves performance in the Ts65Dn, and 4) assessing wheth4r developmental treatment with the neuroprotective agent acetyl-L-carnitine prevents cholinergic degeneration and results in improved cognitive performance in the Ts65Dn mouse. In these studies, we will assess performance in the Morris water maze and a cued and contextual conditioning paradigm. We will also monitor activity over the 24 hour cycle and in elevated plus maze paradigm. Behavioral assessments will be followed up by appropriate neurobiological analyses to determine whether the neurochemical systems impacted by these treatments respond similar in Ts65Dn and control mice.
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