New insights into "GPR40-CREB interaction inadult neurogenesis" specific for primates
New insights into "GPR40-CREB interaction inadult neurogenesis" specific for primates
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DOI：
10.1002/hipo.20951
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发表时间：
2012-04-01
期刊：
影响因子：
3.5
通讯作者：
Yamashima, Tetsumori
中科院分区：
文献类型：
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作者：
Boneva, Nadezhda B.;Yamashima, Tetsumori
已知多不饱和脂肪酸（PUFA），如二十二碳六烯酸（DHA）和花生四烯酸（ARA）与大脑发育密切相关，并且对成人神经发生、学习和精神障碍也具有有益作用。虽然PUFA被证明是G蛋白偶联受体40（GPR 40）的配体，但其在脑中的信号传导机制，特别是在神经原性小生境中，仍然是未知的。使用缺血增强海马神经发生的猴模型，我们研究了GPR 40和磷酸化cAMP反应元件结合蛋白（pCREB），一种参与成人神经发生，学习和记忆的转录因子之间的空间相关性。此外，研究了pCREB的下游基因转录产物脑源性神经营养因子（BDNF）及其受体原肌球蛋白受体激酶B（Trk B）。与作者先前报道的GPR 40的动态变化类似，在短暂性全脑缺血后，Western印迹上pCREB显著上调，并且这与增强的海马神经发生有关。免疫荧光显微镜分析表明，GPR 40和pCREB的表达模式是完全相同的，它们在成熟和新生的神经元以及在星形胶质细胞居住在颗粒下区（SGZ）的共表达。缺血后15 d，SGZ区GPR 40/pCREB双阳性细胞明显增多。成熟形式的BDNF（mBDNF）和TrkB受体在Western印迹上没有显示出显著变化，尽管proBDNF（mBDNF的前体）在第9天达到最大。免疫荧光显微镜显示新生神经元表达BDNF，但不表达TrkB。这些结果共同表明，PUFA，GPR 40，pCREB，BDNF可能参与相同的信号通路，以促进成年灵长类动物海马神经发生。(c)2011 Wiley-Liss，Inc.
Polyunsaturated fatty acids (PUFA), such as docosahexaenoic (DHA) and arachidonic acids (ARA) are known to be closely related to the brain development and also have beneficial effects on adult neurogenesis, learning, and mental disorders. Although PUFA were demonstrated as ligands for G protein-coupled receptor 40 (GPR40), their signaling mechanism in the brain, especially in the neurogenic niche, remains unknown. Using a monkey model of ischemia-enhanced hippocampal neurogenesis, we studied the spatial correlation between GPR40 and the phosphorylated cAMP response element-binding protein (pCREB), a transcription factor involved in adult neurogenesis, learning and memory. Furthermore, the brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB), both being downstream gene transcripts of pCREB, were studied. Similar to the dynamic change of GPR40 as the authors reported previously, pCREB was up-regulated significantly after transient global brain ischemia on Western blots, and this was associated with an enhanced hippocampal neurogenesis. Immunofluorescence microscopic analysis showed that GPR40 and pCREB expression patterns were completely identical, and they were coexpressed in both mature and newborn neurons as well as in the astrocytes residing in the subgranular zone (SGZ). GPR40/pCREB double-positive cells significantly increased in the SGZ on day 15 after ischemia. The mature form of BDNF (mBDNF) and TrkB receptor showed no remarkable changes on Western blots, although proBDNF (precursor of mBDNF) was maximal on day 9. Immunofluorescence microscopy showed that the newborn neurons expressed BDNF, but not TrkB. These results altogether suggest that PUFA, GPR40, pCREB, and BDNF may be engaged in the same signaling pathway to promote neurogenesis in the adult primate hippocampus. (c) 2011 Wiley-Liss, Inc.