The mitogen-activated protein kinase (MAPK) isoforms ERK and p38 MAPK are believed to play opposing roles in long-term synaptic facilitation (LTF) induced by serotonin (5-HT) in Aplysia. To fully understand their roles, however, it is necessary to consider the dynamics of ERK and p38 MAPK activation. Previous studies determined that activation of ERK occurred ∼45 min after a 5-min pulse of 5-HT treatment. The dynamics of p38 MAPK activation following 5-HT are yet to be elucidated. Here, the activity of p38 MAPK was examined at different times after 5-HT, and the interaction between the ERK and p38 MAPK pathways was investigated. A 5-min pulse of 5-HT induced a transient inhibition of p38 MAPK, followed by a delayed activation between 25 and 45 min. This activation was blocked by a MAPK kinase inhibitor, suggesting that similar pathways are involved in activation of ERK and p38 MAPK. ERK activity decreased shortly after the activation of p38 MAPK. A p38 MAPK inhibitor blocked this decrease in ERK activity, suggesting a causal relationship. The p38 MAPK activity ∼45 min after different stimulus protocols was also characterized. These data were incorporated into a computational model for the induction of LTF. Simulations and empirical data suggest that p38 MAPK together with ERK contribute to the efficacy of spaced stimulus protocols to induce LTF, a correlate of long-term memory. For example, decreased p38 MAPK activity ∼45 min after the first of two sensitizing stimuli might be an important determinant of an optimal inter-stimulus interval for LTF induction.
Significance Statement Mitogen-activated protein kinase (MAPK) pathways play critical roles in mediating diverse forms of synaptic plasticity. Activation of the ERK isoform is required for long-term synaptic facilitation (LTF), whereas the p38 MAPK isoform is required for long-term synaptic depression. Here we used isolated Aplysia sensory neurons (SNs) to confirm and extend previous studies delineating dynamics of ERK and p38 MAPK. We quantified p38 MAPK activity after application of the essential neurotransmitter 5-HT, and explored the crosstalk between p38 MAPK and ERK in SNs. These data were incorporated into a computational model for the induction of LTF. Simulations suggest that p38 MAPK together with ERK contribute to the efficacy of temporally spaced stimulus protocols to induce LTF, a correlate of long-term memory.
Authors report no conflict of interest.
This work was supported by NS019895 and NS073974.