Mesial temporal lobe epilepsy (MTLE) is associated with severe neuronal death and reactive gliosis in hippocampus. However, the molecular mechanisms underlying these pathological changes remain unanswered. ERK has been reported chronically activated in reactive glia of human epileptic hippocampus. In the present study, we investigated which of the downstream signaling molecules of ERK would be involved in MTLE. Western blot analysis demonstrated that CREB and p90RSK were strongly activated in MTLE patients. Increase in the active forms of CREB and p90RSK resulted not only from the increase in their phosphorylation levels but also from the increase in the protein levels. Activation of CREB and p90RSK was noted in the whole subfields of hippocampus with Ammon's horn sclerosis (AHS) representing a distinctive cellular distribution. However, the common major change was present in proliferating reactive astrocytes. In contrast, their activation was not significant in adjacent temporal lobes despite the presence of a number of astrocytes expressing high levels of GFAP. Our results demonstrate that chronic activation CREB and p90RSK in the epileptic hippocampus may be closely associated with the histopathological changes of AHS.