Cultured neurons from Down syndrome (DS, trisomy 21, Ts21) fetuses and from fetuses of an animal model for DS, the trisomy 16 (Ts16) mouse, demonstrate many comparable abnormal electrical and biochemical properties. The hippocampus of another animal model, the Ts65Dn mouse, demonstrates abnormal long-term potentiation and depression, thus disturbed synaptic plasticity. Mental retardation in DS may be related to disturbed neuronal electrical properties and neuroplasticity. (1) The gene encoding the NR2A subunit of the NMDA receptor is on mouse chromosome 16, syntetic with human chromosome 21. Its expression is increased 2.5-fold in cultured Ts16 embryonic hippocampal neurons, but their NMDA-evoked currents are not altered. (2) Cultured tongue muscle cells from the Ts16 mouse model of DS have abnormal potassium and chloride membrane conductances. If present in DS muscle, such abnormalities may account for the hypotonia in this disorder. (3) Myoinositol, which is elevated in the DS brain, also is elevated in the brain of the Ts65Dn mouse model for DS. This model thus can be used to study the effect of such elevation on signal transduction and the phosphatidylinositol cycle.