Division of Cellular Neurobiology, Zoological Institute, Technische Universität Braunschweig, D-38106 Braunschweig, Germany.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
Proc Natl Acad Sci U S A. 2017 May 23;114(21):5527-5532. doi: 10.1073/pnas.1613700114. Epub 2017 May 8.
Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.
神经元群体中可塑性阈值的动态调节对于长期可塑性和记忆的形成至关重要，其通过如易化作用等机制来实现。易化作用调节突触，使其发生变化，这些变化是在生理和病理条件下储存记忆的必要前提。在这里，我们发现，在淀粉样前体蛋白（APP）/早老素-1（PS1）小鼠（3-4 月龄）中，一种阿尔茨海默病（AD）的显著小鼠模型，晚期长时程增强（LTP；L-LTP）及其关联的可塑性机制，如突触标记和捕获（STC），在症状前小鼠中已经受损。有趣的是，晚期长时程抑制（LTD；L-LTD）没有受到影响，但在这些小鼠中，LTP 和 LTD 的正关联相互作用，即交叉捕获，发生了改变。这些神经元中肌醇 1,4,5-三磷酸受体（RyRs）的易化作用激活恢复了 L-LTP 和 STC。我们提出，RyR 介导的易化作用机制可以被认为是一种可能的治疗靶点，用于对抗 AD 早期进展过程中神经元网络中的突触损伤。
