Bramham Clive R
Department of Biomedicine and Bergen Mental Health Research Center, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway.
Prog Brain Res. 2007;163:453-71. doi: 10.1016/S0079-6123(07)63025-8.
Synaptic consolidation refers to the development and stabilization of protein synthesis-dependent modifications of synaptic strength as observed during long-term potentiation (LTP) and long-term depression (LTD). Activity-dependent changes in synaptic strength are thought to underlie memory storage and other adaptive responses of the nervous systems of importance in mood stability, reward behavior, and pain control. This chapter focuses on the mechanisms and functions of synaptic consolidation in the dentate gyrus, a critical structure not only in hippocampal memory function, but also in regulation of stress responses and cognitive aspects of depression. Recent evidence suggests that synaptic consolidation at excitatory medial perforant path-granule cell synapses requires brain-derived neurotrophic factor (BDNF) signaling and induction of the immediate early gene activity-regulated cytoskeleton-associated protein (Arc). Arc mRNA is strongly induced and transported to dendritic processes following high-frequency stimulation (HFS) that induces LTP in the rat dentate gyrus in vivo. Sustained synthesis of Arc during a surprisingly protracted time-window is required for hyperphosphorylation of actin depolymerizing factor/cofilin and local expansion of the actin cytoskeleton in vivo. Furthermore, this process of Arc-dependent synaptic consolidation is activated in response to brief infusion of BDNF. Microarray expression profiling has revealed a panel of BDNF-regulated genes that may cooperate with Arc during synaptic consolidation. In addition to regulating gene expression, BDNF signaling modulates the fine localization and biochemical activation of the translation machinery. By modulating the spatial and temporal translation of newly induced (Arc) and constitutively-expressed mRNA in dendrites, BDNF may effectively control the window of synaptic consolidation. Dysregulation of BDNF synthesis and Arc function, specifically within the dentate gyrus, is linked to behavioral symptoms and cognitive deficits in animal models of depression and Alzheimer's disease. Therapeutics strategies targeting synaptic consolidation hold promise for the future.
突触巩固是指在长时程增强（LTP）和长时程抑制（LTD）过程中观察到的、依赖蛋白质合成的突触强度修饰的发展和稳定。突触强度的活动依赖性变化被认为是记忆存储以及神经系统在情绪稳定、奖赏行为和疼痛控制等方面重要的适应性反应的基础。本章重点关注齿状回中突触巩固的机制和功能，齿状回不仅是海马记忆功能的关键结构，也是应激反应调节和抑郁症认知方面的关键结构。最近的证据表明，兴奋性内侧穿通通路 - 颗粒细胞突触处的突触巩固需要脑源性神经营养因子（BDNF）信号传导以及立即早期基因活性调节细胞骨架相关蛋白（Arc）的诱导。在体内诱导大鼠齿状回LTP的高频刺激（HFS）后，Arc mRNA被强烈诱导并转运到树突过程。在体内，肌动蛋白解聚因子 / 丝切蛋白的过度磷酸化和肌动蛋白细胞骨架的局部扩张需要在一个惊人的长时间窗口内持续合成Arc。此外，这种依赖Arc的突触巩固过程在短暂注入BDNF后被激活。微阵列表达谱分析揭示了一组BDNF调节的基因，它们可能在突触巩固过程中与Arc协同作用。除了调节基因表达外，BDNF信号传导还调节翻译机制的精细定位和生化激活。通过调节树突中新诱导（Arc）和组成型表达mRNA的空间和时间翻译，BDNF可以有效地控制突触巩固的窗口。BDNF合成和Arc功能的失调，特别是在齿状回内，与抑郁症和阿尔茨海默病动物模型中的行为症状和认知缺陷有关。针对突触巩固的治疗策略有望用于未来。
