Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression.
Enhanced NMDA receptor tyrosine phosphorylation and increased brain injury following neonatal hypoxia-ischemia in mice with neuronal Fyn overexpression.
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DOI：
10.1016/j.nbd.2012.10.024
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发表时间：
2013-03
影响因子：
6.1
通讯作者：
Jiang X
中科院分区：
文献类型：
--
作者：
Knox R;Zhao C;Miguel-Perez D;Wang S;Yuan J;Ferriero D;Jiang X
Src家族激酶（SFKs）Src和Fyn与发育中的脑中的缺氧缺血（HI）损伤有关。然而，目前还不清楚这些特定的SFKs如何导致脑损伤。使用神经元特异性Fyn过表达（OE）小鼠，我们研究了神经元Fyn在新生儿脑HI中的作用。野生型（WT）和Fyn OE小鼠在出生后第7天使用Vannucci模型进行HI。五天后，使用甲酚紫和铁染色对脑进行评分以评价损伤。在HI后不同时间点用突触后密度（PSD）相关的突触膜蛋白进行Western印迹，并用皮质裂解物进行免疫共沉淀，以确定NMDA受体酪氨酸磷酸化和Fyn激酶活性。与WT同窝小鼠相比，Fyn OE小鼠的死亡率和脑损伤显着更高。神经元Fyn过表达导致突触膜中持续的NR2A和NR2B酪氨酸磷酸化以及增强的NR2B在酪氨酸（Y）1472和Y1252处的磷酸化。这些早期变化与Fyn OE小鼠HI后24 h钙蛋白酶活性高于WT动物相关。我们的研究结果表明Fyn激酶在新生儿HI后神经元死亡中的作用，可能通过上调NMDA受体酪氨酸磷酸化。
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.
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影响因子：
3.5
作者：
Jurd, Rachel;Tretter, Verena;Walker, Joshua;Brandon, Nicholas J.;Moss, Stephen J.
通讯作者：
Moss, Stephen J.
影响因子：
4.8
作者：
Atkinson, EA;Ostergaard, H;Bleackley, RC
通讯作者：
Bleackley, RC
影响因子：
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作者：
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通讯作者：
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影响因子：
6.1
作者：
DeRidder, MN;Simon, MJ;Meaney, DF
通讯作者：
Meaney, DF
影响因子：
5.3
作者：
Hayashi, T;Huganir, RL
通讯作者：
Huganir, RL