Synaptotagmin-3 interactions with GluA2 mediate brain damage and impair functional recovery in stroke

Synaptotagmin III (Syt3) is a Ca²⁺-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca²⁺-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.