Homeostatic Synaptic Scaling Is Regulated by Protein SUMOylation

Tim J Craig,Nadia Jaafari,Milos M Petrovic,Philip P Rubin,Jack R Mellor,Jeremy M Henley

doi:10.1074/jbc.m112.356337

Abstract

Homeostatic scaling allows neurons to alter synaptic transmission to compensate for changes in network activity. Here, we show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating (where SUMO is small ubiquitin-like modifier) enzyme SENP1, leading to a consequent increase in protein SUMOylation. Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a SUMO substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression. Thus, protein SUMOylation plays an important and previously unsuspected role in synaptic trafficking of AMPARs that underlies homeostatic scaling.

Highlights

We show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating enzyme SENP1, leading to a consequent increase in protein SUMOylation
Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a small ubiquitin-like modifier (SUMO) substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression
We further show that SUMOylation of Arc is a key regulator of AMPAR trafficking in synaptic scaling

Summary

Background

Results: Synaptic scaling elicited by suppression of neuronal activity decreases the deSUMOylating enzyme SENP1; overexpression of SENP1 prevents synaptic scaling. We show that suppression of network activity with tetrodotoxin, which increases surface expression of AMPA receptors (AMPARs), dramatically reduces levels of the deSUMOylating (where SUMO is small ubiquitin-like modifier) enzyme SENP1, leading to a consequent increase in protein SUMOylation. Overexpression of the catalytic domain of SENP1 prevents this scaling effect, and we identify Arc as a SUMO substrate involved in the tetrodotoxin-induced increase in AMPAR surface expression. Protein SUMOylation plays an important and previously unsuspected role in synaptic trafficking of AMPARs that underlies homeostatic scaling. AMPA receptors (AMPARs) mediate most fast excitatory synaptic transmission in the central nervous system, and their regulated trafficking underlies NMDA receptor-dependent long-term potentiation and long-term depression [1]. On the other hand, prolonged inhibition of synaptic activity decreases Arc levels, which leads to reduced endocytosis and increased

Synaptic Scaling and SUMOylation

EXPERIMENTAL PROCEDURES

RESULTS AND DISCUSSION

ADDITIONS AND CORRECTIONS