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Long-lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. To answer whether and how different temporal patterns select different signaling pathways for ERK activation, we developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP induction. We show that calcium and cAMP work synergistically to activate ERK and that stimuli given with large inter-trial intervals activate more ERK than shorter intervals. Furthermore, these pathways contribute to different dynamics of ERK activation. These results suggest that signaling pathways with different temporal sensitivity facilitate ERK activation to diversity of temporal patterns.

Long lasting long-term potentiation (L-LTP) is a cellular mechanism of learning and memory storage. Studies have demonstrated a requirement for the extracellular signal-regulated kinase (ERK) activation in L-LTP produced by a diversity of temporal stimulation patterns. Multiple signaling pathways converge to activate ERK, with different pathways being required for different stimulation patterns. We addressed the critical questions of whether maximal activation of ERK requires multiple pathways, and whether different temporal patterns select different signaling pathways for ERK activation. We developed a computational model of five signaling pathways (including two novel pathways) leading to ERK activation during L-LTP. Simulations show that calcium and cAMP work synergistically to activate ERK, and that stimuli given with large inter-trial intervals activate more ERK than shorter intervals, a temporal sensitivity similar to PKA but contrary to CaMKII. These results suggest that signaling pathways with different temporal sensitivity facilitate ERK activation to diversity of temporal patterns.

No abstract