Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury
Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury
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DOI：
10.1016/j.neulet.2009.04.064
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发表时间：
2009-08-07
影响因子：
2.5
通讯作者：
Dietrich, W. Dalton
中科院分区：
文献类型：
--
作者：
Atkins, Coleen M.;Falo, M. Cristina;Dietrich, W. Dalton
创伤性脑损伤(TBI)激活了海马区的几个蛋白激酶信号通路，这些信号通路对海马区依赖记忆的形成至关重要。尤其是细胞外信号调节激酶(ERK)，这是一种在海马依赖学习过程中被激活的蛋白激酶，在脑损伤后被瞬时激活。然而，脑外伤患者在最初的损伤后会经历几个月到几年的海马区依赖的认知障碍。虽然ERK的基础激活水平在脑损伤后数小时内恢复到假水平，但我们推测，脑损伤后ERK的激活可能受到损害。成年雄性Spraogue-Dawley大鼠接受假手术或中度矢状面旁液压冲击脑损伤。在术后2、8、12周，将假手术组和脑外伤动物的同侧海马区切片。在含氧人工脑脊液中恢复2 h后，用谷氨酸或氯化钾去极化刺激海马脑片，然后用Western blotting分析磷酸化、活化的ERK及其下游效应因子之一的转录因子cAMP反应元件结合蛋白(CREB)。我们发现，与假手术组相比，在伤后2、8、12周，S刺激谷氨酸或氯化钾去极化后，大鼠海马脑片ERK(p<；0.05)和CREB(p<；0.05)的活性明显降低。尽管创伤后12周磷酸化CREB的基础水平下降，但在伤后2、8或12周，磷酸化的ERK或总ERK的基础水平没有显著变化。这些结果表明，颅脑损伤通过ERK-CREB通路在海马区导致慢性信号缺陷。(C)2009爱思唯尔爱尔兰有限公司。保留所有权利。
Traumatic brain injury (TBI) activates several protein kinase signaling pathways in the hippocampus that are critical for hippocampal-dependent memory formation. In particular, extracellular signal-regulated kinase (ERK), a protein kinase activated during and necessary for hippocampal-dependent learning, is transiently activated after TBI. However, TBI patients experience hippocampal-dependent cognitive deficits that occur for several months to years after the initial injury. Although basal activation levels of ERK return to sham levels within hours after TBI, we hypothesized that activation of ERK may be impaired after TBI. Adult male Sprague-Dawley rats received either sham surgery or moderate parasagittal fluid-percussion brain injury. At 2, 8, or 12 weeks after surgery, the ipsilateral hippocampi of sham surgery and TBI animals were sectioned into transverse slices. After 2 h of recovery in oxygenated artificial cerebrospinal fluid, the hippocampal slices were stimulated with glutamate or KCl depolarization, then analyzed by western blotting for phosphorylated, activated ERK and one of its downstream effectors, the transcription factor cAMP response element-binding protein (CREB). We found that activation of ERK (p < 0.05) and CREB (p < 0.05) after 30 s of glutamate stimulation or KCl depolarization was decreased in hippocampal slices from animals at 2, 8, or 12 weeks after TBI as compared to sham animals. Basal levels of phosphorylated or total ERK were not significantly altered at 2, 8, or 12 weeks after TBI, although basal levels of phosphorylated CREB were decreased 12 weeks post-trauma. These results suggest that TBI results in chronic signaling deficits through the ERK-CREB pathway in the hippocampus. (C) 2009 Elsevier Ireland Ltd. All rights reserved.