Animal Model: The Ts65Dn mouse, a genetic model of human Down syndrome (DS) (trisomy 21), is trisomic for the segment of murine chromosome 16 that is homologous to human chromosome 21. It demonstrates abnormal learning of spatial tasks. Electrophysiological recording from the isolated hippocampus from this mouse demonstrated abnormal long-term potentiation (LTP) and long term depression (LTD), models for learning and memory, compared with the hippocampus from normal diploid mice. In vivo 1H magnetic resonance spectroscopy and direct chemical analysis of excised tissue showed an increased level of myoinositol in brains of Ts65Dn compared with control mice, consistent with the location of the myoinositol transporter gene on human chromosome 21 and murine chromosome 16. As myoinositol participates in phosphoinositide signaling involving phospholipase C, abnormal phosphoinositide signaling may contribute to mental retardation in DS, and can be examined in a mouse model of this disorder. The trisomic condition represents widespread dysfunction of membrane electrical activity. In another mouse model of DS, the full trisomy 16 mouse, altered activated potassium and chloride conductances were demonstrated by whole cell patch clamp in fetal tongue muscle. Humans: In vivo 1H magnetic resonance spectroscopy demonstrated elevated myoinositol in the brain of young adult DS subjects, further suggesting that an abnormal phosphoinositide cycle contributes to mental retardation in DS. Brain myoinositol was further elevated in older DS subjects (more than 40 years), in which Alzheimer disease (AD) neuropathology has been demonstrated. As AD itself is accompanied by high brain myoinositol, a high level might be used as a marker of AD in subjects genetically at risk for disease but not clinically demented.