We investigated the phenomenon of long-term potentiation (LTP) in a genetic model of Down Syndrome, the segmental trisomy mouse (Ts65Dn). Ts65Dn mice survive to adulthood and have an extra chromosome that contains a segment of chromosome 16 homologous to human chromosome 21. In this study, field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 area of in vitro hippocampal slices from diploid and Ts65Dn mice, and LTP was induced by a single tetanizing pulse train (1 sec in duration) at 100 Hz. The hippocampus from both young (2 months) and older (9 months) Ts65Dn mice had a reduced LTP over a period of 60 min compared with LTP in age-matched controls. This finding may explain the reported behavioral and learning impairments in Ts65Dn mice; it suggests that this mouse model can be used to study the role of altered synaptic plasticity in mental retardation of Down Syndrome.