Potassium Clearance in Optic Nerve: A Multidomain Model.

Background: Ion and water transport in the central nervous system (CNS) is governed by tightly coupled mechanisms involving electrodiffusion, osmotic pressure, and fluid convection. Disruptions to these processes are implicated in pathological conditions. Understanding the coordinated roles of glial cells and perivascular spaces in regulating ionic and fluid homeostasis is essential for interpreting neural function and dysfunction.

Methods: We developed a multicompartment model of the optic nerve incorporating axons, glial cells, extracellular space (ECS), and three perivascular compartments (arterial, venous, and capillary-associated). The model integrates electrodiffusion of ions, osmotic water transport, and convection, while enforcing electroneutrality and compartmental volume conservation. Numerical simulations were performed using a finite volume method under axisymmetric geometry, and parameter sensitivity was explored through variations in glial membrane conductance, connexin permeability, and aquaporin-4 (AQP4) expression.

Results: The simulations reveal that potassium released from axons during stimulation is cleared via glial uptake and redistributed through electric drift within glial syncytia. The perivascular pathway provides a secondary route for potassium and water clearance. Decreased glial conductance leads to abnormal firing in unstimulated axons, mimicking epileptiform activity, while reduced connexin coupling increases dependence on perivascular drainage. Changes in AQP4 expression had limited effect on ionic homeostasis in the current model.

Conclusions: This model provides a biophysically consistent framework to study ionic-fluid coupling in CNS microcirculation. It demonstrates how glial and perivascular compartments cooperate to maintain extracellular potassium balance. The findings offer insight into the mechanisms underlying pathological K⁺ accumulation and suggest potential therapeutic targets involving glial modulation and perivascular enhancement. The framework is extensible to other brain regions and conditions involving impaired clearance or excitability.