DYNAMIC CHANGES IN THE COMPOSITION OF THE AP-1 TRANSCRIPTION FACTOR DNA-BINDING ACTIVITY IN RAT-BRAIN FOLLOWING KAINATE-INDUCED SEIZURES AND CELL-DEATH

Kainate, a potent excitatory and neurotoxic agent, has also proved use ful in studies on other glutamate-driven phenomena, such as neuronal p lasticity. Long-term effects of kainate are apparently dependent on it s influence on the expression of various genes, including those encodi ng the AP-1 transcription factor, consisting of proteins belonging to the Fos and Jun families. In our studies we analysed c-fos, fos B, c-j un, jun B and jun D mRNA levels as well as a functional feature of AP- 1, its DNA-binding activity, in the rat brain following systemic injec tion of kainate. Two phases of elevated AP-1 DNA-binding activity were observed in the hippocampus and entorhinal cortex, and were correlate d with period of seizures (2 and 6 h after kainate injection) and neur on damage (48 - 72 h). At 72 h after kainate treatment DNA fragmentati on, believed to be diagnostic of apoptotic processes typical of progra mmed cell death phenomena, was noted. Two and six hours after the trea tment, AP-1 consisted predominantly of Fos B, c-Fos, Fra-2 and Jun B, while at 72 h Jun D constituted the major AP-1 component in place of J un B, and no c-Fos was detected. Only a slight AP-1 increase was seen 24 h after kainate treatment. In the sensory cortex, only the late pha se of AP-1 elevation was detected. Contrary to AP-1, no effect of kain ate on levels of two other transcription factors, CREB/ATF (cAMP-respo nsive element binding proteins) and OCT (octamer element DNA-binding a ctivity) was seen. However, the level of OCT DNA-binding activity was higher in the sensory cortex than in other two structures examined. Th ese data point to a selective effect of kainate on AP-1 in brain struc tures known to be particularly vulnerable to kainate, and suggest a ro le of AP-1 transcription factor, and more selectively Jun D protein, i n kainate-driven programmed neuronal death.