Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O'Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR ([alpha]-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.