Epilepsy, a common neurological disorder afflicting humans of all ages, is largely incurable at present. Understanding the molecular basis of epileptogenesis could lead to the development of an effective prophylaxis. Studies of kindling, an animal model of complex partial epilepsy, have shown that activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and the induces expression of the immediate early gene (IEG), c-fos, are necessary for optimal induction of lifelong structural and functional plasticity. The objective of this proposal is to analyze some of the molecular events linking NMDA receptor activation to induction expression of the IEG, c-fos, in an in vitro model. Work in my preceptor's laboratory has demonstrated that in dentate gyrus neurons in vitro NMDA receptor activation induces transcriptional activation of c-fos in a Ca2+, phospholipase A2 (PLA2) and cycloozygenase (COX) requiring manner. Moreover, NMDA receptor activation stimulates the synthesis of prostaglandin F2alpha (PGF2alpha), which in turn in required or NMDA-mediated transcriptional activation of c-fos. I will use in situ hybridization, immunocytochemical, and pharmacologic methods to test alternative hypotheses addressing how PGF2alpha conveys signals from NMDA receptors at the cell surface to the transcriptional activation of c-fos in the nucleus.
