Metaplasticity of synaptic tagging and capture and its implications for maintaining long-term memory in normal and diseased neural networks

突触标记和捕获(Synaptic Tagging and Capture，STC)是细胞水平联想记忆形成的重要模式之一。根据这一STC假说，弱记忆形成产生了依赖于时间的突触标记/标记，这些标记可能捕捉到由于附近突触网络中平行的强记忆输入而获得的记忆相关蛋白。这一过程导致了各自弱记忆的巩固。我们中的一人参与了STC中一些关键机制和分子的鉴定(Sajikumar等人，2005b；Sajikumar等人，2007年)。然而，目前还不清楚记忆是如何通过STC随时间擦除而巩固的。我们提出了一种新的神经网络记忆擦除机制：记忆的突触竞争/分配阶段。根据我们的假设，如果记忆蛋白的可用性稀缺，神经元群体将竞争这些蛋白，而竞争的伙伴表现出几乎相似的可塑性阈值。因此，随着时间的推移，巩固的记忆会被抹去。另一方面，我们的模型预测，能够在突触竞争中幸存下来的突触群体，将有更好的机会在不受干扰的情况下编码长期记忆。了解突触竞争的细胞机制对于寻找合适的治疗药物预防记忆丧失非常重要。在我们的研究中，我们将使用Ryanodine受体(RyR)或代谢性受体介导的化塑，并分析化塑诱导蛋白PKMzeta在防止突触竞争中的作用。了解记忆竞争的阶段和性质将为老年性痴呆的发病提供新的见解，并提供令人困惑的问题，即为什么一些人无论年龄都有敏锐的记忆力，为什么另一些人没有导致阿尔茨海默病(AD)。此外，我们将探索通过在阿尔茨海默氏病的神经网络水平上进行靶向，将化塑性作为改善记忆的治疗策略的可能性。

Synaptic tagging and capture (STC) is one of the prominent models of associative memory formation at the cellular level. In line with this STC hypothesis, weak memory formation creates time-dependent synaptic tags/marks that might capture memory related proteins available due to a parallel strong memory input in a nearby synaptic network. This process results in the consolidation of the respective weak memory. One of us was involved in the identification of some of the key mechanisms and molecules in STC (Sajikumar et al., 2005b; Sajikumar et al., 2007). However, it is still unclear how memory consolidated through STC erases with time. We propose a new mechanism for the erasure of memory in neural networks: synaptic competition / distribution phase of memory. According to our hypothesis, a neuronal population will compete for memory proteins if the availability of these proteins is scarce, and the competing partners exhibit nearly similar plasticity thresholds. In consequence, consolidated memories are erased over the time. On the other hand, our model predicts that a synaptic population, which is able to survive synaptic competition, will have a better chance to code long-term memory without disruption. Understanding the cellular mechanisms of synaptic competition is important for finding appropriate therapeutic agents for preventing memory loss. In our studies, we will use ryanodine receptor (RYR) or metabotropic receptor mediated metaplasticity and analyze the role of metaplasticity induced protein PKMzeta for preventing synaptic competition. Understanding the phase and properties of competition of memory will provide new insight into the onset of age related dementia and the puzzling question of why some people have sharp memory irrespective of age and why others have not leading to Alzheimers disease (AD). In addition, we will explore the possibility of using metaplasticity as a therapeutic strategy for improving memory by targeting the neural network level in Alzheimers disease.