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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-03, Vol.117 (9), p.4948-4958
• Main Authors: Yong, Adeline J. H., Tan, Han L., Zhu, Qianwen, Bygrave, Alexei M., Johnson, Richard C., Huganir, Richard L.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - metabolism; Animals; Biological Sciences; Glutamate receptors; GRIP1 protein; Hebbian plasticity; Homeostasis - physiology; Homeostatic plasticity; Long-term potentiation; Male; Mice; Mice, Knockout; Nerve Tissue Proteins - metabolism; Neural networks; Neuronal Plasticity - physiology; Neuroplasticity; Phosphorylation; Plasticity; Protein Transport; Proteins; Receptors, AMPA - metabolism; Synapses; Synapses - metabolism; Synaptic plasticity; Tyrosine; Tyrosine - metabolism; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1918436117

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.