Abstract
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.