Institute of Biophysics, National Research Council, Palermo, Italy.
Institute of Neuroinformatics, University of Zurich and ETH Zurich, Zurich, Switzerland.
PLoS Comput Biol. 2019 Apr 24;15(4):e1006975. doi: 10.1371/journal.pcbi.1006975. eCollection 2019 Apr.
Across the mammalian nervous system, neurotrophins control synaptic plasticity, neuromodulation, and neuronal growth. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is known to promote structural and functional synaptic plasticity in the hippocampus, the cerebral cortex, and many other brain areas. In recent years, a wealth of data has been accumulated revealing the paramount importance of BDNF for neuronal function. BDNF signaling gives rise to multiple complex signaling pathways that mediate neuronal survival and differentiation during development, and formation of new memories. These different roles of BDNF for neuronal function have essential consequences if BDNF signaling in the brain is reduced. Thus, BDNF knock-out mice or mice that are deficient in BDNF receptor signaling via TrkB and p75 receptors show deficits in neuronal development, synaptic plasticity, and memory formation. Accordingly, BDNF signaling dysfunctions are associated with many neurological and neurodegenerative conditions including Alzheimer's and Huntington's disease. However, despite the widespread implications of BDNF-dependent signaling in synaptic plasticity in healthy and pathological conditions, the interplay of the involved different biochemical pathways at the synaptic level remained mostly unknown. In this paper, we investigated the role of BDNF/TrkB signaling in spike-timing dependent plasticity (STDP) in rodent hippocampus CA1 pyramidal cells, by implementing the first subcellular model of BDNF regulated, spike timing-dependent long-term potentiation (t-LTP). The model is based on previously published experimental findings on STDP and accounts for the observed magnitude, time course, stimulation pattern and BDNF-dependence of t-LTP. It allows interpreting the main experimental findings concerning specific biomolecular processes, and it can be expanded to take into account more detailed biochemical reactions. The results point out a few predictions on how to enhance LTP induction in such a way to rescue or improve cognitive functions under pathological conditions.
在哺乳动物神经系统中，神经营养因子控制着突触可塑性、神经调制和神经元生长。脑源性神经营养因子（BDNF）是一种已知的能够促进海马体、大脑皮层和许多其他脑区的结构和功能突触可塑性的神经营养因子。近年来，大量数据积累表明 BDNF 对神经元功能至关重要。BDNF 信号转导产生了多种复杂的信号通路，介导了发育过程中的神经元存活和分化，以及新记忆的形成。如果大脑中的 BDNF 信号转导减少，BDNF 对神经元功能的这些不同作用将产生重要后果。因此，BDNF 敲除小鼠或 TrkB 和 p75 受体缺乏 BDNF 受体信号的小鼠在神经元发育、突触可塑性和记忆形成方面存在缺陷。因此，BDNF 信号转导功能障碍与许多神经和神经退行性疾病有关，包括阿尔茨海默病和亨廷顿病。然而，尽管 BDNF 依赖的信号转导在健康和病理条件下的突触可塑性中具有广泛的影响，但涉及的不同生化途径在突触水平上的相互作用在很大程度上仍然未知。在本文中，我们通过在啮齿动物海马 CA1 锥体神经元中实施第一个 BDNF 调节的、基于尖峰时间的长时程增强（t-LTP）的亚细胞模型，研究了 BDNF/TrkB 信号转导在尖峰时间依赖性可塑性（STDP）中的作用。该模型基于以前关于 STDP 的实验发现，并考虑到了观察到的 t-LTP 的幅度、时程、刺激模式和 BDNF 依赖性。它允许解释关于特定生物分子过程的主要实验发现，并可以扩展到考虑更详细的生化反应。研究结果指出了一些关于如何增强 LTP 诱导的预测，以便在病理条件下挽救或改善认知功能。
