当前位置: X-MOL 学术Front. Comput. Neurosci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation
Frontiers in Computational Neuroscience ( IF 3.2 ) Pub Date : 2020-12-16 , DOI: 10.3389/fncom.2020.569349
Paul Smolen , Douglas A. Baxter , John H. Byrne

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or “tag” synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.

中文翻译:

比较维持晚期 LTP 和长期记忆的理论:激酶反馈通路和突触再激活作用的计算分析

一个基本的神经科学问题是,鉴于作为长期突触增强 (LTP) 或“标记”突触符合 LTP 表达基础的蛋白质周转,记忆是如何从几天到一生保持的。一个可能的解决方案依赖于突触正反馈回路,主要包括 Ca2+/钙调蛋白激酶 II (CaMKII) 的持续激活和蛋白激酶 M ζ (PKMζ) 的自激活合成。数据还表明,基于神经元组件或印迹内反复突触重新激活的正反馈对于维持记忆是必要的。这些机制的相对重要性是有争议的。为了探索每种机制对于维持记忆是必要或足够的可能性,我们用一个简化的模型模拟了 LTP 的维持,该模型结合了持续激酶激活、突触标记、和优先重新激活强突触,并分析了最近数据的影响。我们模拟了三个模型变体,每个模型都通过一个反馈回路维持 LTP:自主、自激活 PKMζ 合成(模型变体 I);自激活 CamKII(模型变体 II);和强化突触的反复再激活(模型变体 III)。变体 I 预测,对于 LTP 的成功维持,要么 1)PKMζ 有助于突触标记,要么 2)在独立于 PKMζ 的维持过程中持续存在低组成性标记水平,或 3)LTP 的维持独立于标记。变体 II 维持 LTP 并表明持续的 CaMKII 激活可以维持 PKMζ 活性,这是以前未考虑过的前馈相互作用。然而,我们注意到挑战 CaMKII 反馈回路的数据。在变体 III 突触再激活驱动器中,从而预测 CamKII 和其他必需激酶的反复或持续激活,这似乎有助于 PKMζ 水平的持续升高。因此,预计重新激活将维持突触标记和可塑性相关蛋白质的结合。我们还建议(模型变体 IV)突触再激活和自主激酶激活可以协同维持 LTP。我们提出了可以区分这些维护机制的实验。我们还建议(模型变体 IV)突触再激活和自主激酶激活可以协同维持 LTP。我们提出了可以区分这些维护机制的实验。我们还建议(模型变体 IV)突触再激活和自主激酶激活可以协同维持 LTP。我们提出了可以区分这些维护机制的实验。
更新日期:2020-12-16
down
wechat
bug