Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia–ischemia in mice with neuronal Fyn overexpression

Renatta Knox; Chong Zhao; Dario Miguel-Perez; Steven Wang; Jinwei Yuan; Donna Ferriero; Xiangning Jiang

Neurobiology of Disease (Mar 2013)

Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia–ischemia in mice with neuronal Fyn overexpression

Renatta Knox,
Chong Zhao,
Dario Miguel-Perez,
Steven Wang,
Jinwei Yuan,
Donna Ferriero,
Xiangning Jiang

Affiliations

Renatta Knox: Department of Neurology, University of California, San Francisco, CA, 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA, 94158, USA; Medical Scientist Training Program, University of California, San Francisco, CA, 94158, USA
Chong Zhao: Department of Neurology, University of California, San Francisco, CA, 94158, USA
Dario Miguel-Perez: Department of Neurology, University of California, San Francisco, CA, 94158, USA
Steven Wang: Department of Neurology, University of California, San Francisco, CA, 94158, USA
Jinwei Yuan: Icon Clinical Research, Redwood City, CA 94065, USA
Donna Ferriero: Department of Neurology, University of California, San Francisco, CA, 94158, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, CA, 94158, USA; Department of Pediatrics, University of California, San Francisco, CA, 94158, USA
Xiangning Jiang: Department of Neurology, University of California, San Francisco, CA, 94158, USA; Corresponding author at: Department of Neurology, University of California, San Francisco, 675 Nelson Rising Lane, Room 494, P.O. Box 0663, San Francisco, CA 94158, USA. Fax: +1 415 502 7325.

Journal volume & issue: Vol. 51
pp. 113 – 119

Abstract

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The Src family kinases (SFKs) Src and Fyn are implicated in hypoxic–ischemic (HI) injury in the developing brain. However, it is unclear how these particular SFKs contribute to brain injury. Using neuron-specific Fyn overexpressing (OE) mice, we investigated the role of neuronal Fyn in neonatal brain HI. Wild type (WT) and Fyn OE mice were subjected to HI using the Vannucci model at postnatal day 7. Brains were scored five days later for evaluation of damage using cresyl violet and iron staining. Western blotting with postsynaptic density (PSD)-associated synaptic membrane proteins and co-immunoprecipitation with cortical lysates were performed at various time points after HI to determine NMDA receptor tyrosine phosphorylation and Fyn kinase activity. Fyn OE mice had significantly higher mortality and brain injury compared to their WT littermates. Neuronal Fyn overexpression led to sustained NR2A and NR2B tyrosine phosphorylation and enhanced NR2B phosphorylation at tyrosine (Y) 1472 and Y1252 in synaptic membranes. These early changes correlated with higher calpain activity 24 h after HI in Fyn OE mice relative to WT animals. Our findings suggest a role for Fyn kinase in neuronal death after neonatal HI, possibly via up-regulation of NMDA receptor tyrosine phosphorylation.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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