S100 beta, a calcium-binding brain specific protein, may affect both brain development and hippocampal long-term potentiation. S100 beta levels are elevated in Down syndrome (DS), and the gene for S100 beta is located on chromosome 21, which is duplicated in DS. To test the hypothesis that, elevated levels of S100 beta cause behavioral alterations in a mammalian system, 3 transgenic mouse lines with multiple copies of the human gene for S100 beta were derived and behaviorally tested. The spontaneous alteration behavior of transgenic and normal littermate mice were compared in a T maze during a 15-trial test. The overall alteration rate was found to be significantly decreased in the transgenic mice compared with their normal littermates. The S100 beta transgenic mouse model offers one of the first opportunities to investigate the relation between overexpression of a human chromosome 21 gene product and abnormal behavior and brain function.