NMDAR-dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity

Dipen Rajgor, Tom Sanderson, Mascia Amici, Graham L Collingridge, Jonathan Hanley*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

10 Citations (Scopus)
281 Downloads (Pure)

Abstract

MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.
Original languageEnglish
Article numbere97943
Number of pages21
JournalEMBO Journal
Volume37
Issue number11
Early online date30 Apr 2018
DOIs
Publication statusPublished - 1 Jun 2018

Keywords

  • Argonaute
  • dendritic spine
  • MicroRNA
  • phosphorylation
  • synaptic plasticity
  • translation

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