{Reference Type}: Journal Article
{Title}: Precise timing of ERK phosphorylation/dephosphorylation determines the outcome of trial repetition during long-term memory formation.
{Author}: Kukushkin NV;Tabassum T;Carew TJ;
{Journal}: Proc Natl Acad Sci U S A
{Volume}: 119
{Issue}: 40
{Year}: 10 2022 4
{Factor}: 12.779
{DOI}: 10.1073/pnas.2210478119
{Abstract}: Two-trial learning in Aplysia reveals nonlinear interactions between training trials: A single trial has no effect, but two precisely spaced trials induce long-term memory. Extracellularly regulated kinase (ERK) activity is essential for intertrial interactions, but the mechanism remains unresolved. A combination of immunochemical and optogenetic tools reveals unexpected complexity of ERK signaling during the induction of long-term synaptic facilitation by two spaced pulses of serotonin (5-hydroxytryptamine, 5HT). Specifically, dual ERK phosphorylation at its activating TxY motif is accompanied by dephosphorylation at the pT position, leading to a buildup of inactive, singly phosphorylated pY-ERK. Phosphorylation and dephosphorylation occur concurrently but scale differently with varying 5HT concentrations, predicting that mixed two-trial protocols involving both "strong" and "weak" 5HT pulses should be sensitive to the precise order and timing of trials. Indeed, long-term synaptic facilitation is induced only when weak pulses precede strong, not vice versa. This may represent a physiological mechanism to prioritize memory of escalating threats.