Homeostatic Synaptic Scaling Is Regulated by Protein SUMOylation

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. Background: SUMOylation regulates many cell pathways. Results: Synaptic scaling elicited by suppression of neuronal activity decreases the deSUMOylating enzyme SENP1; overexpression of SENP1 prevents synaptic scaling. Conclusion: SUMOylation is required for AMPA receptor trafficking underlying scaling, an important form of neuronal plasticity. Significance: Regulation of synaptic dynamics and plasticity is fundamental to understanding brain function and dysfunction.