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.
Haifeng Lu  1 ,  Shujun Chen  1 ,  Qianqian Nie  1 ,  Qun Xue  2 ,  Hua Fan  3 ,  Yiqing Wang  1 ,  Shenghao Fan  1 ,  Juehua Zhu  1 ,  Haitao Shen  4 ,  Haiying Li  4 ,  Qi Fang  1 ,  Jianqiang Ni  1 ,  Gang Chen  5
Affiliations
  • 1. Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China.
  • 2. Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China. Electronic address: [email protected].
  • 3. The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471000, Henan, China.
  • 4. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China.
  • 5. Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China. Electronic address: [email protected].
PMID: 36892998 DOI: 10.1016/j.celrep.2023.112233
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.
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