Neuron–Astrocyte Coupling Regulates Ion Homeostasis and Neuronal Excitability in a Multi-Compartment Model

Abstract

Introduction Neuronal excitability depends on transmembrane gradients of sodium (Na), potassium (K), and chloride (Cl). Astrocytes contribute to ionic homeostasis by regulating extracellular ion concentrations through membrane channels, transporters, and spatial buffering across their extended processes and syncytial networks [1]. Among the main pathways are K uptake via astrocytic Na/K-ATPase (aNKA) and Kir4.1 channels, and Cl regulation via ClC-2 channels and GABA-A receptors [2,3]. Although these mechanisms have been studied individually, their combined influence on extracellular ion dynamics and neuronal activity in the coupled neuron–extracellular space (ECS)–astrocyte system remains unclear. Methods We developed a multi-compartment model consisting of a neuron (N) interacting with an astrocytic shell (A) through a local extracellular space (E). Astrocytes are coupled via gap junctions to a distal glial syncytium (G), which exchanges ions with a bath reservoir (B). Neuronal dynamics follow Hodgkin–Huxley kinetics with voltage-gated and leak Na, K and Cl channels, muscarinic currents, neuron Na/K-ATPase (nNKA), and K–Cl cotransporters (KCC), while the ECS tracks ionic accumulation. Astrocytes include aNKA, Kir4.1 channels, Cl fluxes, and glutamate (GLT-1) and GABA (GAT) transporters. Simulations quantify how neuronal activity alters extracellular ion concentrations and how astrocytic regulation feeds back onto neuronal excitability. Results Coupling the neuron compartment to a closed extracellular space reveals strong activity-dependent ionic accumulation. During sustained stimulation, extracellular K progressively increases, shifting reversal potentials and altering neuronal firing dynamics until the system enters depolarization block. In the neuron–ECS configuration this depolarized state is stable, preventing recovery of the initial resting equilibrium. Introducing astrocytic mechanisms delay depolarization block through the interplay between K uptake and Cl fluxes. When distal buffering pathways are included, ionic redistribution through astrocytic networks and extracellular diffusion toward a bath reservoir restores the hyperpolarized resting state. Discussion These results highlight the importance of astrocyte-mediated ion regulation for stabilizing neuronal excitability. While neuronal mechanisms alone cannot recover from activity-induced ionic imbalance, astrocytic buffering reduces extracellular K accumulation and delays depolarization block. Recovery of the resting equilibrium requires distal ion redistribution through gap-junction–coupled astrocytic networks and extracellular diffusion toward distal reservoirs [4]. The efficiency of this process depends on the rate of intercellular exchange and parenchyma tortuosity, which constrains ionic diffusion. Together, these mechanisms provide a dynamical framework for how astrocytes regulate ionostasis and maintain stable neuronal activity. Acknowledgments We acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) [Grant ID: RGPIN 2024 04333] References [1] Verkhratsky, A. & Nedergaard, M. (2018). Physiology of Astroglia. Physiological Reviews, 98(1), 239-389. doi: 10.1152/physrev.00042.2016[2] Kofuji, P. & Newman, E. (2004). Potassium buffering in the central nervous system. Neuroscience, 129(4), 1043-1054. doi: 10.1016/j.neuroscience.2004.06.008[3] Untiet, V. & Verkhratsky, A. (2024). How astrocytic chloride modulates brain states. BioEssays, 46(6). doi: 10.1002/bies.202400004[4] Hübel, N. & Dahlem, M. (2014). Dynamics from Seconds to Hours in Hodgkin-Huxley Model with Time-Dependent Ion Concentrations and Buffer Reservoirs. PLoS Computational Biology, 10(12), e1003941. doi: 10.1371/journal.pcbi.1003941