UCSF

Neonatal brain hypoxia-ischemia (HI) is an important cause of morbidity and mortality in infants and children. However, there are few treatments. We have recently demonstrated that Src Family Kinase (SFK) activity and NMDA receptor (NMDAR) tyrosine phosphorylation are increased following neonatal HI in mice. Inhibition of SFKs provides neuroprotection against HI. However, it is unknown which particular SFKs contribute to neonatal HI brain injury or the molecular mechanisms by which SFKs worsen brain injury. We used two transgenic mouse models to determine the role of Fyn and Fyn-mediated NR2B tyrosine phosphorylation in neonatal HI. We found that neuronal Fyn overexpression leads to increased brain injury and mortality in response to neonatal HI. These changes correlated with elevated NMDAR tyrosine phosphorylation and increased calpain activity. Mutation of tyrosine 1472 of NR2B to phenylalanine (Y1472F) resulted in decreased brain injury, NR2B tyrosine phosphorylation at specific residues, and calpain activity following HI. In vitro Y1472F neurons had less generation of reactive oxygen species and cell death in response to NMDA and glutamate. Taken together, these studies implicate Fyn and tyrosine phosphorylation of the NR2B subunit in neonatal hypoxic-ischemic brain injury and encourage the development of therapies targeting Fyn in neonatal HI.