Interestingly, S100B knockout mice have been reported to enhance spatial memory and context dependent fear memory. Recently, S100B-RAGE interaction has been implicated in the brain in vivo in a condition that mimics epileptic seizures by kainic acid administration. RAGE KO mice have been generated by a multiple number of laboratories. Although RAGE KO mice have been utilized in biochemical and physiological experiments to address the roles of RAGE in progression of various pathological conditions, consequences of lacking RAGE in normal condition have hardly been addressed. In this study, we performed a series of standard behavioral tests to identify the phenotype of RAGE KO mice. Among the series of behavioral tests, the most striking behavioral difference was observed in the home cage activity. RAGE KO mice displayed,30% higher activity in darkness on day 1 and persistently higher activity Ginkgolide-B during the seven days of observation. In addition, auditory startle Magnoflorine-iodide response assessment resulted in a higher sensitivity to auditory signal in KO mice. The higher sensitivity to auditory signal provides an explanation for the increased prepulse inhibition ratio in KO animals and auditory cue-dependent classical fear conditioning. The animals�� curiosity or anxiety should be excluded from the subject of the difference, as the open field test and the elevated plus maze test yielded no significantly different scores. Our results indicate that deletion of RAGE has minimal effects on the animals�� spatial learning ability. Therefore, it appears that RAGE does not have a critical importance in synaptic plasticity of the hippocampus and the associated areas. In fact, long-term potentiation in the entorhinal cortex has been reported to be not affected in RAGE KO mice. By contrast, genetic manipulations of S100B, a ligand for RAGE, result in more visible effects on learning and memory. S100B KO mice improve performance in spatial learning and become more sensitive to context-dependent fear conditioning, whereas S100B overexpressing transgenic mice have inferior performance in spatial learning.