Prostaglandin F2 alpha is required for NMDA receptor-mediated induction of c-fos mRNA in dentate gyrus neurons

Activation of NMDA receptors has been linked to a diversity of lasting physiological and pathological changes in the mammalian nervous system, The cellular and molecular mechanisms underlying permanent modifications of nervous system structure and function after brief episodes of neuronal activity are unknown, Immediate-early genes (IEGs) have been implicated in the conversion of short-term stimuli to long-term changes in cellular phenotype by regulation of gene expression. The intracellular signaling pathways coupling activation of receptors at the cell surface with induction of IEGs in the nucleus are incompletely understood, NMDA produces a striking increase in the IEG c-fos in dentate gyrus (DG) neurons in vitro; this induction is dependent, in part, on the arachidonic acid cascade. Here we show that NMDA receptor activation triggers the synthesis of the prostaglandins PGF(2 alpha) and PGE(2), but not PGD(2), in rat cerebral cortical neurons in vitro. We further demonstrate that PGF(2 alpha), but not PGE(2) or PGD(2), is necessary but not sufficient for NMDA induction of c-fos mRNA in DG neurons. These findings provide insight into the molecular events coupling activation of the NMDA receptor with regulation of the IEG c-fos and identify the diffusable messenger PGF(2 alpha) as obligatory for NMDA receptor-mediated transcription of a nuclear IEG.