Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation

Long-term potentiation (LTP) is a cellular model for persistent synaptic pl asticity in the mammalian brain. Like several forms of memory, long-lasting LTP requires cAMP-mediated activation of protein kinase A (PKA) and is dep endent on gene transcription. Consequently, activity-dependent genes such a s c-fos that contain cAMP response elements (CREs) in their 5' regulatory r egion have been studied intensely. More recently, arg3.1/ arc became of int erest, because after synaptic stimulation, arg3.1/arc mRNA is rapidly induc ed and distributed to dendritic processes and may be locally translated the re to facilitate synapse-specific modifications. However, to date nothing i s known about the signaling mechanisms involved in the induction of this ge ne. Here we report that arg3.1/arc is robustly induced with LTP stimulation even at intensities that are not sufficient to activate c-fos expression. Unlike c-fos, the 5' regulatory region of arg3.1/arc does not contain a CRE consensus sequence and arg3.1/arc is unresponsive to cAMP in NIH3T3 and Ne uro2a cells. However, in PC12 cells and primary cultures of hippocampal neu rons, arg3.1/arc can be induced by cAMP and calcium. This induction require s the activity of PKA and mitogen-activated protein kinase, suggesting a ne uron-specific pathway for the activation of arg3.1/arc expression.