Department of Restorative Neurosurgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Hippocampus. 2012 Apr;22(4):896-905. doi: 10.1002/hipo.20951. Epub 2011 May 18.
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.
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，对成年神经发生、学习和精神障碍也有有益的影响。尽管已经证明 PUFA 是 G 蛋白偶联受体 40（GPR40）的配体，但它们在大脑中的信号机制，特别是在神经发生龛中，仍然未知。本研究使用增强海马神经发生的猴子模型，研究了 GPR40 与磷酸化 cAMP 反应元件结合蛋白（pCREB）之间的空间相关性，pCREB 是参与成年神经发生、学习和记忆的转录因子。此外，还研究了脑源性神经营养因子（BDNF）及其受体原肌球蛋白受体激酶 B（TrkB），它们都是 pCREB 的下游基因转录物。与作者之前报道的 GPR40 的动态变化类似，Western blot 显示短暂性全脑缺血后 pCREB 显著上调，这与海马神经发生增强有关。免疫荧光显微镜分析显示，GPR40 和 pCREB 的表达模式完全相同，它们在成熟和新生神经元以及位于颗粒下区（SGZ）的星形胶质细胞中均有表达。缺血后 15 天，SGZ 中的 GPR40/pCREB 双阳性细胞显著增加。Western blot 显示成熟形式的 BDNF（mBDNF）和 TrkB 受体没有明显变化，尽管前体 BDNF（mBDNF 的前体）在第 9 天达到最大值。免疫荧光显微镜显示新生神经元表达 BDNF，但不表达 TrkB。这些结果表明，PUFA、GPR40、pCREB 和 BDNF 可能参与同一信号通路，促进成年灵长类动物海马体的神经发生。
