The Lundbeck Foundation Research Centre, MIND, Danish Research Institute of Translational Neuroscience DANDRITE, Nordic EMBL Partnership, Department of Biomedicine, Aarhus University, DK-8000C Aarhus, Denmark.
Learn Mem. 2013 Sep 1;20(9):499-504. doi: 10.1101/lm.032045.113.
BDNF-induced signaling is essential for the development of the central nervous system and critical for plasticity in adults. Mature BDNF signals through TrkB, while its precursor proBDNF employs p75(NTR), resulting in activation of signaling cascades with opposite effects on neuronal survival, growth cone decisions, and synaptic plasticity. Accordingly, variations in the genes encoding BDNF and its receptors sometimes have opposing influences in psychiatric disorders, and despite the vast literature, consensus is lacking about the behavioral consequences of disrupting the activity of the BDNF system in mice. To dissect the behavioral traits affected by dysfunctional BDNF/TrkB vs. proBDNF/p75(NTR) activity, we studied Bdnf(+/-), Ntrk2(+/-), and Ngfr(-/-) mice in parallel with respect to exploratory behavior, anxiety, startle, and fear acquisition. Our data reveal that the effect of proBDNF/BDNF and its receptors on behavior is more complex than expected. Strikingly, receptor-deficient mice displayed increased risk-taking behavior in the open field and elevated plus maze, whereas lack of proBDNF/BDNF had the opposite effect on mouse behavior. On the other hand, although TrkB signaling is instrumental for acquisition of fear memory in an inhibitory avoidance experiment, lack of p75(NTR) or proBDNF/BDNF conferred increased memory in this task. Importantly, none of the genotypes displayed any deficits in startle reflex, indicating unimpaired response to shock. The combined data illustrate an apparent paradox in the role of the BDNF system in controlling complex behavior and suggest that the individual components may also engage independently in separate signaling pathways.
BDNF 诱导的信号对于中枢神经系统的发育至关重要，并且对于成年人的可塑性也至关重要。成熟的 BDNF 通过 TrkB 发出信号，而其前体 proBDNF 则采用 p75（NTR），从而激活具有相反作用的信号级联反应，对神经元存活、生长锥决定和突触可塑性产生影响。因此，编码 BDNF 和其受体的基因变异有时在精神疾病中有相反的影响，尽管文献丰富，但对于破坏 BDNF 系统在小鼠中的活性的行为后果仍缺乏共识。为了剖析由 BDNF/TrkB 与 proBDNF/p75（NTR）活性失调引起的行为特征，我们平行研究了 Bdnf(+/-)、Ntrk2(+/-)和 Ngfr(-/-)小鼠的探索行为、焦虑、惊跳和恐惧获得。我们的数据表明，proBDNF/BDNF 及其受体对行为的影响比预期的要复杂。引人注目的是，受体缺陷型小鼠在开阔场和高架十字迷宫中表现出增加的冒险行为，而缺乏 proBDNF/BDNF 对小鼠行为则有相反的影响。另一方面，尽管 TrkB 信号对于抑制性回避实验中的恐惧记忆获得是必不可少的，但缺乏 p75（NTR）或 proBDNF/BDNF 赋予了该任务中增加的记忆。重要的是，没有任何基因型在惊跳反射方面显示出任何缺陷，表明对电击的反应没有受损。综合数据说明了 BDNF 系统在控制复杂行为中的作用明显存在悖论，并表明各个成分也可能独立参与独立的信号通路。
