S100 beta, a calcium-binding brain specific protein, may affect brain development and long-term potentiation. Its gene maps to a region of chromosome 21 duplicated in Down's Syndrome (DS), and its levels are elevated in DS. To test the hypothesis that elevated S100 beta levels cause brain dysfunction in a mammalian system, transgenic mice carrying multiple copies of the human S100 beta gene have been generated and their locomotory patterns are analyzed in open field situations. Female-specific hyperactivity was observed in 2-month-old and in 12-month-old transgenic mice, which rules out the previous speculation that postmenopausal hormonal changes constitute a necessary factor in this behavioral abnormality. Analysis of temporal patterns of activity showed a profound abnormality in transgenic females: the initially elevated activity quickly habituated in males and in normal females, however, its level remained high in the transgenic females throughout the 9-min recording session. These observations are compatible with the suggestion that hippocampal function is abnormal in the females of S100 beta transgenic mice.