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<p>Hyperexcitability and hypersynchronization of neuronal networks are hallmark pathological features in the early stages of Alzheimer’s disease (AD). Astrocyte dysfunction mediated by amyloid-beta (Aβ) is considered a key contributor to the induction of network hyperexcitability and hypersynchrony. Currently, there are no effective treatments for AD-related neuronal network hyperexcitability and hypersynchronization. However, recent advances in optogenetic stimulation and ceftriaxone medication offer promising therapeutic avenues. Based on this, we develop an Aβ-mediated astrocyte-neuronal network model incorporating both optogenetic stimulation and ceftriaxone treatment. The model integrates three Aβ-related pathological effects and two distinct Natronomonas halorhodopsin (NpHR)-based optogenetic stimulation protocols. Furthermore, building on physiological experimental data, we innovatively simulate the effect of ceftriaxone on astrocytic glutamate transporters. In terms of results, our model successfully recapitulates the pathological phenomena of neuronal hyperexcitability and hypersynchrony observed in AD. To evaluate the treatment efficacy, we propose two quantitative metrics to assess the effects of different therapeutic strategies on network hyperexcitability and hypersynchronization. The results show that not all optogenetic stimulation protocols ameliorate network hyperexcitability; rather, stimulation with lower light intensity and lower duty cycles yields better outcomes. Furthermore, Poisson-type optogenetic stimulation demonstrates superior therapeutic effects compared to periodic stimulation. Moreover, we find that ceftriaxone is more effective than optogenetic stimulation in mitigating neuronal hyperexcitability and hypersynchronization. Interestingly, ceftriaxone also significantly reduces synaptic and extrasynaptic glutamate toxicity levels. These results underscore the strong therapeutic potential of ceftriaxone in treating neuronal network hyperexcitability, aligning with findings from physiological experiments. In summary, our study provides a modeling framework for understanding experimental observations of Aβ-induced network abnormal dynamics and offers potential insights for developing diverse treatments targeting hyperexcitability and hypersynchronization in AD.</p>

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Diverse therapeutic control of Aβ-mediated hyperexcitability and hypersynchronization in astrocyte-neuronal networks

  • 期刊论文

  • 发表日期：

    2026年4月3日

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  • YuPeng Li,
  • XiaoLi Yang

摘要

Hyperexcitability and hypersynchronization of neuronal networks are hallmark pathological features in the early stages of Alzheimer’s disease (AD). Astrocyte dysfunction mediated by amyloid-beta (Aβ) is considered a key contributor to the induction of network hyperexcitability and hypersynchrony. Currently, there are no effective treatments for AD-related neuronal network hyperexcitability and hypersynchronization. However, recent advances in optogenetic stimulation and ceftriaxone medication offer promising therapeutic avenues. Based on this, we develop an Aβ-mediated astrocyte-neuronal network model incorporating both optogenetic stimulation and ceftriaxone treatment. The model integrates three Aβ-related pathological effects and two distinct Natronomonas halorhodopsin (NpHR)-based optogenetic stimulation protocols. Furthermore, building on physiological experimental data, we innovatively simulate the effect of ceftriaxone on astrocytic glutamate transporters. In terms of results, our model successfully recapitulates the pathological phenomena of neuronal hyperexcitability and hypersynchrony observed in AD. To evaluate the treatment efficacy, we propose two quantitative metrics to assess the effects of different therapeutic strategies on network hyperexcitability and hypersynchronization. The results show that not all optogenetic stimulation protocols ameliorate network hyperexcitability; rather, stimulation with lower light intensity and lower duty cycles yields better outcomes. Furthermore, Poisson-type optogenetic stimulation demonstrates superior therapeutic effects compared to periodic stimulation. Moreover, we find that ceftriaxone is more effective than optogenetic stimulation in mitigating neuronal hyperexcitability and hypersynchronization. Interestingly, ceftriaxone also significantly reduces synaptic and extrasynaptic glutamate toxicity levels. These results underscore the strong therapeutic potential of ceftriaxone in treating neuronal network hyperexcitability, aligning with findings from physiological experiments. In summary, our study provides a modeling framework for understanding experimental observations of Aβ-induced network abnormal dynamics and offers potential insights for developing diverse treatments targeting hyperexcitability and hypersynchronization in AD.