Li YuPeng, Yang XiaoLi, Yang Hao, Kurths Jürgen
Shaanxi Normal University, School of Mathematics and Statistics, Xi'an 710062, People's Republic of China.
Potsdam Institute for Climate Impact Research, Telegraphenberg, Potsdam D-14415, Germany.
Phys Rev E. 2025 Jun;111(6-1):064419. doi: 10.1103/1r82-x54p.
Neuronal hyperexcitability is a key feature in the early stages of Alzheimer's disease (AD). However, the underlying mechanisms have not been fully elucidated, particularly the impact of amyloid β-peptide (Aβ)-mediated astrocyte dysfunction on neuronal hyperexcitability. Building upon recent experiments demonstrating that Aβ induces neuronal hyperexcitability by reducing glutamate uptake and increasing glutamate release in astrocytes, we have developed here a neurocomputational model of the Aβ-mediated astrocyte-neuron tripartite synapse. This model included a presynaptic neuron, a postsynaptic neuron, and an astrocyte, with information exchange between the neurons and the astrocyte facilitated by glutamate. The astrocytic glutamate pathways depended on synapse-cleft-oriented glutamate transporters (GLT-syn) and extra-synapse-oriented glutamate transporters (GLT-ess), metabotropic glutamate receptors (mGluR), and glutamate gliotransmitter release (Glio-Rel). Our numerical simulations have indicated that Aβ-induced down-regulation of astrocytic glutamate transporters and increased glutamate gliotransmitter release result in neuronal hyperexcitability, characterized by increased neuronal firing rate, enhanced presynaptic neuronal glutamate release intensity, and elevated postsynaptic neuron calcium concentration, which are in good agreement with previous experimental findings. Furthermore, our study has revealed that Aβ primarily induces hyperexcitation of presynaptic neurons through the Glio-Rel and GLT-ess pathways and hyperexcitation of postsynaptic neurons through the GLT-syn, Glio-Rel, and GLT-ess pathways. Additionally, we have found a strong, monotonically increasing correlation between the average firing rate of neurons and the average amplitude (or frequency) of astrocyte calcium oscillations, suggesting a close relationship between neuronal hyperexcitability and astrocyte calcium dysfunction. In conclusion, these results not only support experimental observations but also provide crucial insights into understanding neuronal hyperexcitation in AD.
神经元兴奋性过高是阿尔茨海默病（AD）早期的一个关键特征。然而，其潜在机制尚未完全阐明，尤其是淀粉样β肽（Aβ）介导的星形胶质细胞功能障碍对神经元兴奋性过高的影响。基于最近的实验表明Aβ通过减少星形胶质细胞对谷氨酸的摄取和增加谷氨酸释放来诱导神经元兴奋性过高，我们在此开发了一个Aβ介导的星形胶质细胞 - 神经元三联突触的神经计算模型。该模型包括一个突触前神经元、一个突触后神经元和一个星形胶质细胞，神经元和星形胶质细胞之间的信息交换由谷氨酸促进。星形胶质细胞的谷氨酸途径依赖于面向突触间隙的谷氨酸转运体（GLT - syn）和面向突触外的谷氨酸转运体（GLT - ess）、代谢型谷氨酸受体（mGluR）以及谷氨酸神经递质释放（Glio - Rel）。我们的数值模拟表明，Aβ诱导的星形胶质细胞谷氨酸转运体下调和谷氨酸神经递质释放增加导致神经元兴奋性过高，其特征为神经元放电频率增加、突触前神经元谷氨酸释放强度增强以及突触后神经元钙浓度升高，这与先前的实验结果高度一致。此外，我们的研究表明，Aβ主要通过Glio - Rel和GLT - ess途径诱导突触前神经元兴奋性过高，通过GLT - syn、Glio - Rel和GLT - ess途径诱导突触后神经元兴奋性过高。此外，我们发现神经元的平均放电频率与星形胶质细胞钙振荡的平均幅度（或频率）之间存在强烈的、单调增加的相关性，这表明神经元兴奋性过高与星形胶质细胞钙功能障碍之间存在密切关系。总之，这些结果不仅支持了实验观察，还为理解AD中的神经元兴奋性过高提供了关键见解。
