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

Cell Rep. 2023 Mar 28;42(3):112233. doi: 10.1016/j.celrep.2023.112233. Epub 2023 Mar 8.

Abstract

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.

Keywords: CP: Neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins* / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Neuronal Plasticity
  • Stroke*
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Synaptotagmins
  • Syt3 protein, mouse
  • glutamate receptor ionotropic, AMPA 2