Long-term dynamic profiles of cognitive kinases induced by different learning protocols.

Learning is associated with activation of multiple protein kinases, but few details are known about the activation dynamics in response to different learning protocols. We addressed this issue by examining the long-term dynamics of kinases critical for long-term synaptic facilitation (LTF) of the Aplysia sensorimotor synapse. Three serotonin (5-HT) protocols have been found to induce LTF with distinct effectiveness: the five-pulse regular-spaced Standard protocol; the five-pulse irregular-spaced Enhanced protocol; and the two-pulse protocol with an interval of 45 min. We previously compared long-term dynamics of the mitogen-activated protein kinase (MAPK) isoform ERK after these protocols. Here we examined the long-term dynamics of additional kinases critical for LTF: p38 MAPK, protein kinase A (PKA), and p90 ribosomal S6 kinase (RSK). All four kinases showed complex dynamics of activity during 24 h, with a first wave of increase occurring shortly after 5-HT treatment and ending within 5 h, and a second wave from ∼5 to 18 h. After the standard and two-pulse protocols, all kinase activities returned toward basal at 24 h, but after the Enhanced protocol, some remained elevated at 24 h. Interactions and multiple feedback loops among the kinase pathways, and with the growth factors Aplysia neurotrophin (NT) and transforming growth factor-β (TGF-β), contribute to development of molecular clocks underlying these complex dynamics. These results help to delineate the molecular mechanisms underlying the induction of LTF and provide insights that may help design improved training protocols for induction and maintenance of LTF and long-term memory.