Systemic administration of kainate (KA), a glutamate receptor agonist, causes robust and recurrent seizures in the rat and can cause permanent damage in the central nervous system (CNS), specifically in the limbic system. KA induced epileptic seizures increase the expression of immediate-early genes such as c-fos and fos-related antigens (FRA) in the CNS and genes encoding for neuropeptides such as dynorphin and enkephalin with a specific pattern. Thus, the long-term consequence of KA treatment in the expression of immediate-early genes and neuropeptides and damage in the limbic system can provide an opportunity to explore the role of FRA and neuropeptides in long-term biochemical changes and the mechanism of neuroexcitoxicity and plasticity. Three major efforts have been undertaken to study the long-term genomic effects of KA in the rat brain. (A) Long-term expression of FRA after KA, (B) Long-term expression of enkephalin and dynorphin after KA, and (C) cloning the 35-kDa FRA induced by KA treatment. We have characterized a 35-kDa FRA and AP-1 DNA binding activity in rat brain 5 months after KA treatment and determined the anatomical locale and time-course of FRA expression in rat brains for the first 5 months after KA injection. We also demonstrated that the expression of PENK and PDYN genes can be regulated by KA and that KA-induced increases in expressions of these two genes persist for at least 5 months. Time courses of ENK and DYN expressions in the hippocampus are closely correlated with the expression of FRA immunoreactivity after KA injections. Finally, we successfully cloned a FRA gene which encoding the 62-63-kDa and 33-35-kDa proteins recognized the FRA antibody. The functional significance is under investigation.
