Alzheimer's disease is a formidable health challenge due to lack of effective therapeutic modalities. The excitation/inhibition imbalance in the early stage of Alzheimer's disease can be potentially considered as a central link between structural brain pathology and cognitive dysfunction. However, the role and effects of reactive astrocytes in the neuronal excitability in early Alzheimer's disease remain unclear. Here, we present a tripartite synaptic model integrating the interactions between neurons and astrocytes than can clarify the role of astrocytes in the regulation of excitation/inhibition. Our model integrates the cation channel transient receptor potential ankyrin 1, whose activation triggers calcium influx, thereby enhancing the fidelity of astrocyte calcium dynamics. Constrained by physiological data, we demonstrate that amyloid-β can activate astrocytes to release glial neurotransmitters, thereby mediating the hyperexcitability of nearby neurons. We also investigate the astrocyte-mediated symbiosis of two neurotransmitters, glutamate and gamma-aminobutyric acid, at the glutamatergic synapse in the context of Alzheimer's disease, to predict the inhibitory compensatory response to excitotoxicity. During excitotoxicity, astrocytes can use the coupling of the excitatory amino acid transporter and gamma-aminobutyric acid transporter to control the concentration ratio of glutamate and gamma-aminobutyric acid in the synaptic cleft, and may convert both through the intracellular gamma-aminobutyric acid synthesis pathway. Our findings reveal that the coding efficiency of neurons diminished as the effects of amyloid-β deepened, establishing a direct link between the pathological features of Alzheimer's disease and cognitive dysfunction. These simulations suggest that astrocytes play a critical role in regulating the neuronal excitation/inhibition balance in the early stage of Alzheimer's disease, thereby influencing the subsequent processes of information transmission, learning, and memory. The pathways characterized by our model present potential therapeutic targets for Alzheimer's disease.
Li et al. (Thu,) studied this question.