of Work:
AIMS : Kainic acid (KA), a rigid analog of the excitatory amino acid glutamate, has been widely used to create an excellent animal model for studying human temporal lobe epilepsy. A single injection of KA to rats induces long-lasting recurrent seizures and almost permanent biochemical and morphological changes in the brain which resemble the alterations found in patients with temporal lobe epilepsy. The purpose of this study was to elucidate the molecular mechanisms underlying the regulation of the long-term changes of two classes of opioid peptides, enkephalins and dynorphins, which are important neuromodulators regulating the seizure threshold in the hippocampus. Accomplishments: We have previously shown that a single injection of KA produces large increases in the abundance of the mRNAs encoding for both proenkephalin (PENK) and prodynorphin (PDYN) in the hippocampus which last for 4-7 days. Recent long-term studies showed that 2-3 weeks after KA treatment, there is a second phase of increase in PENK mRNA, but not PDYN mRNA, which lasts for at least one year. To study the transcriptional regulation of the PENK gene, we have examined several transcription factors, namely, CREB, NFkB, and AP-1. One of the most interesting findings from this series of studies was the unexpectedly prolonged expression of AP-1 DNA-binding activity in the hippocampus after a single injection of KA. The increase of AP-1 DNA-binding activity parallels the time course of that for PENK mRNA and also lasts at least one year. Detailed analyses of this long-lasting AP-1 complex revealed that the main components of the AP-1 complex are Jun D and a novel 35 kDa FRA (Fos related antigen). Further study indicated that these two AP-1 transcription factors and PENK mRNA colocalize in the same neurons in the hippocampus, suggesting the possibility that these two events are related. Since enkephalin is known to produce seizures in the hippocampus, this study provides some neurochemical basis for the long-lasting recurrent seizures seen in KA-treated rats. Further studies in this line of research should provide insights into the mechanisms underlying the permanent changes in the seizure threshold seen in temporal lobe epileptic patients and help with the development of therapeutic interventions.
