Regulation of amygdala-dependent learning by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol-3-kinase
Regulation of amygdala-dependent learning by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol-3-kinase
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DOI：
10.1038/sj.npp.1300830
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发表时间：
2006-02-01
影响因子：
7.6
通讯作者：
Gean, PW
中科院分区：
文献类型：
--
作者：
Ou, LC;Gean, PW
这项研究旨在表征脑源性神经营养因子（BDNF）调节恐惧条件反射长期记忆的信号级联。酶联免疫吸附试验（ELISA）和Western印迹分析的组织匀浆取自恐惧条件下的大鼠表明，增加杏仁核的BDNF蛋白水平和其受体TrkB磷酸化。双侧施用TrkB配体清除剂TrkB IgG和Trk特异性酪氨酸激酶抑制剂K252 a至杏仁核损害了恐惧记忆，如用恐惧增强惊吓所测量的。恐惧条件化导致Shc和TrkB、Shc和Ras的结合，活性Ras的增加和丝裂原活化蛋白激酶（MAPK）的磷酸化。BDNF处理杏仁核切片15分钟，活性Ras、MAPK和Akt磷酸化水平增加。BDNF诱导的MAPK磷酸化被MEK抑制剂完全消除，并被法尼基转移酶或磷脂酰肌醇-3激酶（PI-3激酶）抑制剂部分抑制。另一方面，BDNF诱导的Akt磷酸化不受法尼基转移酶或MEK抑制剂的影响，但可以被PI-3激酶抑制剂阻断。总之，这些数据表明，恐惧学习需要BDNF。BDNF的记忆增强作用涉及MAPK和PI-3激酶的激活。杏仁核中BDNF诱导的MAPK磷酸化通过TrkB和Shc结合位点介导。Shc与TrkB的结合导致Ras、Raf和MEK的活化。此外，BDNF还可通过激活PI-3激酶诱导MAPK磷酸化。
This study is designed to characterize the signal cascades by which brain-derived neurotrophic factor ( BDNF) modulates long-term memory of fear conditioning. Enzyme-linked immunosorbent assay ( ELISA) and Western blot analysis of tissue homogenates taken from fear-conditioned rats showed an increase in the amygdala of BDNF protein levels and its receptor TrkB phosphorylation. Bilateral administration of a TrkB ligand scavenger TrkB IgG and a Trk-specific tyrosine kinase inhibitor K252a to the amygdala impaired fear memory, as measured with fear-potentiated startle. Fear conditioning resulted in the association of Shc and TrkB, Shc and Ras, the increase in active Ras and phosphorylation of mitogen-activated protein kinase ( MAPK). Treatment of amygdala slices with BDNF for 15 min increased the levels of active Ras, and MAPK and Akt phosphorylation. BDNF-induced MAPK phosphorylation was completely abolished by MEK inhibitors, and was partially inhibited by farnesyltransferase or phosphatidylinositol-3 kinase (PI-3 kinase) inhibitors. On the other hand, BDNF-induced Akt phosphorylation was unaffected by farnesyltransferase or MEK inhibitors, but could be blocked by PI-3 kinase inhibitors. Together, these data suggest a requirement of BDNF for fear learning. The memory-enhancing effect of BDNF involves the activation of MAPK and PI-3 kinase. BDNF-induced MAPK phosphorylation in the amygdala is mediated via TrkB and the Shc-binding site. Shc binding to TrkB leads to activation of Ras, Raf, and MEK. In addition, BDNF could induce phosphorylation of MAPK via activation of PI-3 kinase.