Gottschalk W A, Jiang H, Tartaglia N, Feng L, Figurov A, Lu B
Unit on Synapse Development and Plasticity National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland 20892-4480, USA.
Learn Mem. 1999 May-Jun;6(3):243-56.
Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-gamma (PLC-gamma) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-gamma. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-gamma, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.
尽管最近的研究表明，脑源性神经营养因子（BDNF）在海马体突触可塑性中发挥着重要作用，但其潜在的信号传导机制在很大程度上仍不清楚。在这里，我们已经确定了介导BDNF对高频突触传递调节作用的信号事件。丝裂原活化蛋白激酶（MAPK）、磷脂酰肌醇-3激酶（PI3K）和磷脂酶C-γ（PLC-γ）是已知在其他系统中介导神经营养因子信号传导的三条信号通路。在新生海马体切片中，应用BDNF可迅速激活MAPK和PI3K，但不激活PLC-γ。BDNF大大减轻了由一连串高频强直刺激（HFS）诱导的CA1突触处的突触疲劳。抑制MAPK和PI3K，而不是PLC-γ，可阻止BDNF对高频突触传递的调节作用。神经营养因子-3（NT-3）是BDNF的近亲，它不激活MAPK或PI3K，对新生海马体中的突触疲劳也没有影响。激活MAPK但不激活PI3激酶的福斯可林，以及激活PI3K但不激活MAPK的睫状神经营养因子（CNTF），均不影响HFS诱导的突触疲劳。用福斯可林和CNTF一起处理切片对突触疲劳仍然没有影响。因此，虽然需要激活MAPK和PI3K，但两者一起并不足以介导BDNF的作用。茴香霉素或环己酰亚胺抑制新蛋白质合成并不能阻止BDNF的作用。这些数据表明，BDNF对高频传递的调节作用独立于蛋白质合成，但需要MAPK和PI3K以及另一条信号通路在海马体中共同发挥作用。
