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Abstract

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.