Persistent increased DNA-binding and expression of serum response factor occur with epilepsy-associated long-term plasticity changes

We have previously shown that NMDA receptor activation during status epilep ticus (SE) is required to produce epilepsy in in vitro and in vivo models. As in human symptomatic epilepsy, the epilepsy in these models is permanent , suggesting that the pathological activation of NMDA receptors causes perm anent plasticity changes in the brain. Ca2+ influx through NMDA receptors i s known to transiently activate a key transcription factor, serum response factor (SRF). Thus, we investigated whether this factor, in terms of its ex pression and ability to bind to the consensus serum response element, was a ltered long term in the pilocarpine model of epilepsy. In hippocampal nucle ar extracts, SRF binding to DNA was significantly increased over saline-inj ected control rats at 24 hr and at 8 weeks after the onset of SE. This incr ease was shown to be the result of significantly elevated levels of SRF. DN A binding was also persistently increased in the cortical, but not in the c erebellar, extracts. Hippocampal expression of SRF was localized to neurons using immunohistochemistry. NMDA receptor activation during SE was require d for these changes to take place, and the spontaneous seizures seen in epi leptic rats did not appear to be responsible for the increase in SRF. The r esults demonstrate that SRF is persistently elevated after SE in the piloca rpine model of epilepsy and support the theory that long-term gene changes in this model occur and are associated with the long-lasting plasticity cha nges that are initiated during epileptogenesis.