The long term goal of this project is to study the molecular mechanisms underlying the transcriptional regulation of two opioid peptides, enkephalins (ENK) and dynorphins (DYN) in the brain. We have previously shown that a single injection of kainic acid (KA), a glutamate receptor agonist which induces seizure convulsions in rats, produces large increases in the abundance of mRNA encoding both proenkephalins (PENK) and prodynorphin (PDYN) in the hippocampus which lasts for 4-7 days. Recent 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 at least for one year. The purpose of this project was to examine the potential transcription factors associated with this long-term expression of the PENK gene after KA treatment. One of the most interesting findings from this series of studies was the unexpectedly prolonged expression of AP-1 DNA-binding activity after a single injection of KA in seizure sensitive brain regions, such as the hippocampus. We found that in two brain regions (the hippocampus and olfactory bulb) the increase in AP-1 DNA-binding activity persisted up to one year, the longest time point investigated. The rapid and transient induction of the AP-1 factors, such as c-Fos, is considered to be the hallmark of immediate-early genes. Therefore, the most exciting finding of our studies was the demonstration that the increase in the AP-1 complex can clearly be long-lasting and perhaps become a permanent phenomenon. The short-term AP-1 complex may mediate the induction of certain genes which respond to stimuli in an acute fashion ranging from minutes to hours. On the other hand,a the long-term AP-1 complex may be associated with the changes in neuronal plasticity which often require protracted time periods ranging from days to months.
