Bingyu Ren

The trafficking of AMPA receptors (AMPARs), including internalization, recycling, and membrane reinsertion, is critical for maintaining synaptic plasticity. Our previous work showed that the microtubule-severing protein Spastin regulates AMPAR surface expression, but the underlying mechanisms remain to be fully elucidated. Here, we demonstrate that deSUMOylated Spastin (Spastin-K427R) enhanced GluA1 recycling and membrane reinsertion and is associated with dendritic spine maturation and excitatory synaptic transmission. Overexpression of Spastin-K427R increased surface GluA1 expression, spine density, and miniature excitatory synaptic currents (mEPSC) amplitude and frequency, with stronger effects than wild-type Spastin. While wild-type Spastin directed GluA1 to both recycling and late endosomes, Spastin-K427R preferentially promoted its localization to Syntaxin 13-associated recycling endosomes and reduced LAMP1-associated degradation. We further identified IST1, an ESCRT-III complex component, as a key mediator of Spastin’s effect. Co-overexpression of IST1 with Spastin enhanced synaptic transmission and spine maturation, whereas IST1 knockdown reduced GluA1 surface levels and abolished Spastin’s effects. Notably, Spastin-K427R exhibited enhanced binding to IST1 than wild-type Spastin. These findings reveal a post-translational mechanism by which the deSUMOylation of Spastin facilitates IST1-dependent AMPAR recycling, contributing to synaptic plasticity regulation. Graphical Abstract