The behavioral differences between RAGE KO and S100B KO imply that RAGE may not be a crucial receptor of S100B for learning and memory. It is, however, noted that attenuation of kainateinduced gamma oscillations in S100B KO has recently been demonstrated to be dependent on activation of RAGE, suggesting a role of RAGE in hyperactive brain states. One potential caveat is that the mice used in the current study have been backcrossed eight times to C57BL6, so that the expected percentage of genetic material from the original strain is below 0.4%.As the KO phenotypes were dependent on presentation of sensory stimulus, RAGE may play an active role in sensory organs or the brain. Immunohistochemical localization of RAGE in the brain has remained Pachymic-acid controversial to date. Furthermore, esRAGE, a Paederoside soluble and secretory form of RAGE, could play an important role. Interestingly, reduced immunoreactivity against esRAGE in CA3 hippocampal neurons were found in Alzheimer��s patients. Future investigations on localization of membrane bound and soluble forms of RAGE, as well as RAGE induced biochemical pathways shall further identify the role of RAGE in the central nervous system. As activation of RAGE accelerates pathological progression of diabetes or Alzheimer��s disease, therapeutic treatments to attenuate activation of RAGE have been suggested and experimented in animal disease or inflammation models. Our results raise a possibility that systemic therapeutic treatments to occlude RAGE activation may have adverse effects as demonstrated by the home cage activity and prepulse inhibition behavioral tests. Further investigations using mice of different background strains and identification of biochemical pathways that elucidates the behavioral phenotypes are needed for better understanding of RAGE in basal states. The economic cost of depression is largely due to related work impairment, disability, and lost productivity from sickness absenteeism and presenteeism. Presenteeism is common, more costly than absenteeism, and may account for up to 80% of depression-related lost productive time.