Tyrosine phosphorylation of the AMPA receptor subunit GluA2 gates homeostatic synaptic plasticity

Adeline J.H. Yong, Han L. Tan, Qianwen Zhu, Alexei M. Bygrave, Richard C. Johnson, Richard L. Huganir

Research output: Contribution to journalArticlepeer-review

Abstract

Hebbian plasticity, comprised of long-term potentiation (LTP) and depression (LTD), allows neurons to encode and respond to specific stimuli; while homeostatic synaptic scaling is a counterbalancing mechanism that enables the maintenance of stable neural circuits. Both types of synaptic plasticity involve the control of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) abundance, which is modulated by AMPAR phosphorylation. To address the necessity of GluA2 phospho-Y876 in synaptic plasticity, we generated phosphodeficient GluA2 Y876F knock-in mice. We show that, while GluA2 phospho-Y876 is not necessary for Hebbian plasticity, it is essential for both in vivo and in vitro homeostatic upscaling. Bidirectional changes in GluA2 phospho-Y876 were observed during homeostatic scaling, with a decrease during downscaling and an increase during upscaling. GluA2 phospho-Y876 is necessary for synaptic accumulation of glutamate receptor interacting protein 1 (GRIP1), a crucial scaffold protein that delivers AMPARs to synapses, during upscaling. Furthermore, increased phosphorylation at GluA2 Y876 increases GluA2 binding to GRIP1. These results demonstrate that AMPAR trafficking during homeostatic upscaling can be gated by a single phosphorylation site on the GluA2 subunit.

Original languageEnglish (US)
Pages (from-to)4948-4958
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number9
DOIs
StatePublished - Mar 3 2020

Keywords

  • AMPAR
  • GRIP1
  • GluA2
  • GluA2 tyrosine phosphorylation
  • Homeostatic plasticity

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Tyrosine phosphorylation of the AMPA receptor subunit GluA2 gates homeostatic synaptic plasticity'. Together they form a unique fingerprint.

Cite this