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The Journal of Neuroscience, October 1, 1999, 19(19):8234-8243

Persistent Increased DNA-Binding and Expression of Serum Response Factor Occur with Epilepsy-Associated Long-Term Plasticity Changes

T. Allen Morris¹, Neda Jafari², Ann C. Rice¹, Olavo Vasconcelos¹, and Robert J. DeLorenzo^{1, 2, 3}

Departments of ¹ Neurology, ² Pharmacology and Toxicology, and ³ Biochemistry and Molecular Biophysics, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

We have previously shown that NMDA receptor activation during status epilepticus (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 permanent plasticity changes in the brain. Ca²⁺ influx through NMDA receptors is known to transiently activate a key transcription factor, serum response factor (SRF). Thus, we investigated whether this factor, in terms of its expression and ability to bind to the consensus serum response element, was altered long term in the pilocarpine model of epilepsy. In hippocampal nuclear extracts, SRF binding to DNA was significantly increased over saline-injected control rats at 24 hr and at 8 weeks after the onset of SE. This increase was shown to be the result of significantly elevated levels of SRF. DNA binding was also persistently increased in the cortical, but not in the cerebellar, extracts. Hippocampal expression of SRF was localized to neurons using immunohistochemistry. NMDA receptor activation during SE was required for these changes to take place, and the spontaneous seizures seen in epileptic rats did not appear to be responsible for the increase in SRF. The results demonstrate that SRF is persistently elevated after SE in the pilocarpine model of epilepsy and support the theory that long-term gene changes in this model occur and are associated with the long-lasting plasticity changes that are initiated during epileptogenesis.

Key words: epilepsy; serum response factor; neuronal plasticity; seizure; status epilepticus; hippocampus; SRF

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19198234-10$05.00/0

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