FEMALE TRANSGENIC MICE CARRYING MULTIPLE COPIES OF THE HUMAN GENE FORS100-BETA ARE HYPERACTIVE

Down syndrome (DS) (trisomy 21) is the most frequent genetic cause of mental retardation in man. The gene coding for the beta subunit of hum an S 100 protein (S100beta) has been mapped to chromosome 2 1. The dim eric form of S100beta may function as a neurotrophic factor in the CNS and may also influence the establishment of hippocampal long-term pot entiation (LTP). To study the behavioral consequences of overexpressio n of S100beta in an animal model, we derived four lines of transgenic mice carrying multiple copies of the human S100beta gene. The human S1 00beta gene was expressed in the brain of these mice in a cell-specifi c and gene-dose-dependent manner. The motor and posture patterns of 16 -month-old transgenic mice and their control (non-transgenic) litterma tes were studied in two tests, open field and bar-crossing, in order t o examine novelty induced exploratory activities. Transgenic female mi ce were significantly hyperactive in both tests in comparison with the ir female control littermates. These differences were independent of t he line of origin of the mice suggesting a causal relationship between the observed hyperactivity and the presence of multiple copies of the integrated human S100beta gene. In contrast, transgenic males were no t hyperactive in comparison with controls. Neither male nor female tra nsgenic mice displayed any coordination defects. We speculate about ho w an interaction between the effects of elevated S100beta levels and f emale specific hormonal changes could have resulted in the observed fe male restricted hyperactivity. Our results establish the first experim ental correlation between overexpression of a chromosome 21 gene produ ct and a behavioral abnormality.