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<p>Epilepsy, characterized by abnormal neuronal hyperexcitability and disrupted ion homeostasis, increasingly appears to involve complex neuron–glia interactions. This study develops a three-compartment computational model encompassing neurons, astrocytes, and the extracellular space to investigate the effects of optogenetic stimulation (OS) of astrocytes expressing channelrhodopsin-2 (ChR2) and optogenetic inhibition (OI) of neurons expressing Archaerhodopsin-T (ArchT). The model integrates dynamic sodium, potassium, and calcium concentrations with explicit Na⁺/K⁺-ATPase and Kir4.1 channel mechanisms to simulate ionic regulation under normal and epileptic conditions. Simulations reveal that astrocytic OS markedly reduces seizure severity by enhancing Na⁺ influx and activating the Na⁺/K⁺-ATPase, thereby accelerating extracellular K⁺ clearance and dampening neuronal excitability. The anticonvulsant effect persists even when astrocytic calcium signaling or Kir4.1 channel function is impaired, underscoring the dominant role of Na⁺/K⁺-ATPase activity. Combined astrocytic stimulation and neuronal inhibition further decrease extracellular potassium and neuronal spiking, indicating a synergistic effect. Pre-seizure astrocyte activation proves substantially more effective than post-onset stimulation. These findings highlight astrocytes as active modulators of brain excitability and identify Na⁺/K⁺-ATPase–driven ion regulation as a key mechanism underlying seizure control, offering a mechanistic basis for glia-targeted optogenetic therapies in drug-resistant epilepsy.</p>

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Nonlinear dynamics of seizure suppression via optogenetic modulation of neuron-astrocyte interaction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月18日

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  • Mozhdeh Maboodi,
  • Abazar Arabameri,
  • Fariba Bahrami

摘要

Epilepsy, characterized by abnormal neuronal hyperexcitability and disrupted ion homeostasis, increasingly appears to involve complex neuron–glia interactions. This study develops a three-compartment computational model encompassing neurons, astrocytes, and the extracellular space to investigate the effects of optogenetic stimulation (OS) of astrocytes expressing channelrhodopsin-2 (ChR2) and optogenetic inhibition (OI) of neurons expressing Archaerhodopsin-T (ArchT). The model integrates dynamic sodium, potassium, and calcium concentrations with explicit Na⁺/K⁺-ATPase and Kir4.1 channel mechanisms to simulate ionic regulation under normal and epileptic conditions. Simulations reveal that astrocytic OS markedly reduces seizure severity by enhancing Na⁺ influx and activating the Na⁺/K⁺-ATPase, thereby accelerating extracellular K⁺ clearance and dampening neuronal excitability. The anticonvulsant effect persists even when astrocytic calcium signaling or Kir4.1 channel function is impaired, underscoring the dominant role of Na⁺/K⁺-ATPase activity. Combined astrocytic stimulation and neuronal inhibition further decrease extracellular potassium and neuronal spiking, indicating a synergistic effect. Pre-seizure astrocyte activation proves substantially more effective than post-onset stimulation. These findings highlight astrocytes as active modulators of brain excitability and identify Na⁺/K⁺-ATPase–driven ion regulation as a key mechanism underlying seizure control, offering a mechanistic basis for glia-targeted optogenetic therapies in drug-resistant epilepsy.