PSD-93 deletion inhibits Fyn-mediated phosphorylation of NR2B and protects against focal cerebral ischemia.
Modification of N-methyl-d-aspartate receptor (NMDAR)-mediated excitotoxicity appears to be a potential target in the treatment of ischemic stroke. Postsynaptic density protein-93 (PSD-93) specifically binds the C-terminal tails of the NMDAR, which is critical to couple NMDAR activity to specific intracellular signaling. This study is to investigate whether PSD-93 disruption displays neuroprotection in a focal ischemic stroke model of adult mice and, if it does, to explore possible mechanisms. It was found that, following middle cerebral artery occlusion (MCAO), PSD-93 knockout (KO) mice manifested significant reductions in infarcted volume, neurological deficits and number of degenerated neurons. PSD-93 deletion also reduced cultured cortical neuronal death caused by glucose and oxygen deprivation (OGD). Ischemic long term potentiation (i-LTP) could not be induced in the PSD-93 KO group and wild type (WT) groups pretreated with either AP-5 (NMDAR inhibitor) or PP2 (Src family inhibitor). PSD-93 KO decreased the phosphorylation of the NR2B at Tyr1472 and the interaction between NR2B and Fyn after MCAO. Together, our study demonstrated that PSD-93 KO confers profound neuroprotection against ischemic brain injury, which probably links to the inhibitory effect on Fyn-mediated phosphorylation of NR2B caused by PSD-93 deletion. These findings may provide a novel avenue for the treatment of ischemic stroke.
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, PR China; Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing, PR China; Diagnosis and Therapy Center of Stroke in Jiangsu Province, PR China.
Meijuan
M
Zhang
Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, PR China.
Qingjie
Q
Li
Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China.
Ling
L
Chen
Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, PR China.
Jie
J
Li
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, PR China; Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing, PR China; Diagnosis and Therapy Center of Stroke in Jiangsu Province, PR China.
Xin
X
Zhang
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, PR China.
Xiang
X
Chen
Department of Neurology, Drum Tower Hospital of Nanjing Medical University, Nanjing, PR China.
Qingxiu
Q
Zhang
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, PR China.
Yuan
Y
Shao
Department of Neurology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, PR China; Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, PR China; Jiangsu Key Laboratory for Molecular Medicine, Nanjing, PR China; Diagnosis and Therapy Center of Stroke in Jiangsu Province, PR China. Electronic address: xuyun20042001@aliyun.com.
Yun
Y
Xu
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051528:Guanylate Kinases / Q000172:deficiency* / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009422:Nervous System Diseases / Q000209:etiology; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C056639:2-amino-5-phosphopentanoic acid; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051528:Guanylate Kinases; D014633:Valine
Fyn; Ischemic stroke; NMDAR; PSD-93; Tyrosine phosphorylation