Bramham Clive R, Messaoudi Elhoucine
Department of Biomedicine, Bergen Mental Health Research Center, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Prog Neurobiol. 2005 Jun;76(2):99-125. doi: 10.1016/j.pneurobio.2005.06.003.
Interest in BDNF as an activity-dependent modulator of neuronal structure and function in the adult brain has intensified in recent years. Localization of BDNF-TrkB to glutamate synapses makes this system attractive as a dynamic, activity-dependent regulator of excitatory transmission and plasticity. Despite individual breakthroughs, an integrated understanding of BDNF function in synaptic plasticity is lacking. Here, we attempt to distill current knowledge of the molecular mechanisms and function of BDNF in LTP. BDNF activates distinct mechanisms to regulate the induction, early maintenance, and late maintenance phases of LTP. Evidence from genetic and pharmacological approaches is reviewed and tabulated. The specific contribution of BDNF depends on the stimulus pattern used to induce LTP, which impacts the duration and perhaps the subcellular site of BDNF release. Particular attention is given to the role of BDNF as a trigger for protein synthesis-dependent late phase LTP--a process referred to as synaptic consolidation. Recent experiments suggest that BDNF activates synaptic consolidation through transcription and rapid dendritic trafficking of mRNA encoded by the immediate early gene, Arc. A model is proposed in which BDNF signaling at glutamate synapses drives the translation of newly transported (Arc) and locally stored (i.e., alphaCaMKII) mRNA in dendrites. In this model BDNF tags synapses for mRNA capture, while Arc translation defines a critical window for synaptic consolidation. The biochemical mechanisms by which BDNF regulates local translation are also discussed. Elucidation of these mechanisms should shed light on a range of adaptive brain responses including memory and mood resilience.
近年来，脑源性神经营养因子（BDNF）作为成人大脑神经元结构和功能的活动依赖性调节剂，受到的关注日益增加。BDNF与酪氨酸激酶受体B（TrkB）定位于谷氨酸突触，这使得该系统作为兴奋性传递和可塑性的动态、活动依赖性调节剂具有吸引力。尽管有个别突破，但对BDNF在突触可塑性中的功能仍缺乏综合理解。在这里，我们试图提炼目前关于BDNF在长时程增强（LTP）中的分子机制和功能的知识。BDNF激活不同机制来调节LTP的诱导、早期维持和晚期维持阶段。对来自遗传学和药理学方法的证据进行了综述并制成表格。BDNF的具体作用取决于用于诱导LTP 的刺激模式，这会影响BDNF释放的持续时间以及可能的亚细胞位点。特别关注BDNF作为蛋白质合成依赖性晚期LTP（一个称为突触巩固的过程）触发因素的作用。最近的实验表明，BDNF通过对即刻早期基因Arc编码的mRNA进行转录和快速树突运输来激活突触巩固。提出了一个模型，其中谷氨酸突触处的BDNF信号驱动新运输的（Arc）和局部储存的（即α-钙/钙调蛋白依赖性蛋白激酶II）mRNA在树突中的翻译。在这个模型中，BDNF标记突触以捕获mRNA，而Arc翻译定义了突触巩固的关键窗口。还讨论了BDNF调节局部翻译的生化机制。对这些机制的阐明应该有助于揭示一系列适应性大脑反应，包括记忆和情绪恢复力。
