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

Haifeng Lu; Shujun Chen; Qianqian Nie; Qun Xue; Hua Fan; Yiqing Wang; Shenghao Fan; Juehua Zhu; Haitao Shen; Haiying Li; Qi Fang; Jianqiang Ni; Gang Chen

Cell Reports (Mar 2023)

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

Haifeng Lu,
Shujun Chen,
Qianqian Nie,
Qun Xue,
Hua Fan,
Yiqing Wang,
Shenghao Fan,
Juehua Zhu,
Haitao Shen,
Haiying Li,
Qi Fang,
Jianqiang Ni,
Gang Chen

Affiliations

Haifeng Lu: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Shujun Chen: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Qianqian Nie: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Qun Xue: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China; Corresponding author
Hua Fan: The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471000, Henan, China
Yiqing Wang: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Shenghao Fan: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Juehua Zhu: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Haitao Shen: 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
Haiying Li: 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
Qi Fang: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Jianqiang Ni: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou 215006, Jiangsu, China; Institute of Stroke Research, Soochow University, Suzhou 215006, Jiangsu, China
Gang Chen: 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; Corresponding author

Journal volume & issue: Vol. 42, no. 3
p. 112233

Abstract

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Summary: 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.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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