Precise timing of ERK phosphorylation/dephosphorylation determines the outcome of trial repetition during long-term memory formation

Nikolay V. Kukushkin, Tasnim Tabassum, Thomas J. Carew

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere2210478119
Pages (from-to)e2210478119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number40
DOIs
StatePublished - Oct 4 2022

Keywords

  • ERK
  • PKA
  • intertrial interactions
  • long-term facilitation
  • phosphatase

ASJC Scopus subject areas

  • General

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