Jȩdrzejewska-Szmek Joanna, Luczak Vincent, Abel Ted, Blackwell Kim T
The Krasnow Institute for Advanced Studies, George Mason University, Fairfax, Virginia, United States of America.
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Comput Biol. 2017 Jul 24;13(7):e1005657. doi: 10.1371/journal.pcbi.1005657. eCollection 2017 Jul.
Long-lasting forms of long-term potentiation (LTP) represent one of the major cellular mechanisms underlying learning and memory. One of the fundamental questions in the field of LTP is why different molecules are critical for long-lasting forms of LTP induced by diverse experimental protocols. Further complexity stems from spatial aspects of signaling networks, such that some molecules function in the dendrite and some are critical in the spine. We investigated whether the diverse experimental evidence can be unified by creating a spatial, mechanistic model of multiple signaling pathways in hippocampal CA1 neurons. Our results show that the combination of activity of several key kinases can predict the occurrence of long-lasting forms of LTP for multiple experimental protocols. Specifically Ca2+/calmodulin activated kinase II, protein kinase A and exchange protein activated by cAMP (Epac) together predict the occurrence of LTP in response to strong stimulation (multiple trains of 100 Hz) or weak stimulation augmented by isoproterenol. Furthermore, our analysis suggests that activation of the β-adrenergic receptor either via canonical (Gs-coupled) or non-canonical (Gi-coupled) pathways underpins most forms of long-lasting LTP. Simulations make the experimentally testable prediction that a complete antagonist of the β-adrenergic receptor will likely block long-lasting LTP in response to strong stimulation. Collectively these results suggest that converging molecular mechanisms allow CA1 neurons to flexibly utilize signaling mechanisms best tuned to temporal pattern of synaptic input to achieve long-lasting LTP and memory storage.
长时程增强(LTP)的持久形式是学习和记忆的主要细胞机制之一。LTP领域的一个基本问题是,为什么不同的分子对于由不同实验方案诱导的LTP持久形式至关重要。信号网络的空间方面进一步增加了复杂性,即一些分子在树突中起作用,而一些分子在棘突中至关重要。我们研究了是否可以通过创建海马CA1神经元中多个信号通路的空间、机制模型来统一各种实验证据。我们的结果表明,几种关键激酶的活性组合可以预测多种实验方案中LTP持久形式的发生。具体而言,Ca2+/钙调蛋白激活激酶II、蛋白激酶A和cAMP激活的交换蛋白(Epac)共同预测了对强刺激(多串100Hz)或异丙肾上腺素增强的弱刺激的LTP发生。此外,我们的分析表明,通过经典(Gs偶联)或非经典(Gi偶联)途径激活β-肾上腺素能受体是大多数持久LTP形式的基础。模拟做出了一个可通过实验验证的预测,即β-肾上腺素能受体的完全拮抗剂可能会阻断对强刺激的持久LTP。这些结果共同表明,趋同的分子机制使CA1神经元能够灵活地利用最适合突触输入时间模式的信号机制,以实现持久的LTP和记忆存储。