Glymphatic Clearance in the Optic Nerve: A Multidomain Electro-osmostic Model

TL;DR

This study presents a comprehensive electro-osmotic model of optic nerve fluid dynamics, elucidating glymphatic clearance mechanisms, the role of astrocytic pathways, and how various parameters influence waste removal efficiency.

Contribution

It introduces a multidomain electro-osmotic model that captures fluid and solute transport in the optic nerve, highlighting the importance of PVS pathways and astrocytic endfeet in glymphatic clearance.

Findings

PVS-mediated export is the main clearance route for solutes.

Lowering AQP4 or PVS permeability increases pressure and reduces clearance.

ECS diffusion rate influences solute clearance speed.

Abstract

Effective metabolic waste clearance and maintaining ionic homeostasis are essential for the health and normal function of the central nervous system. To understand its mechanism and the role of fluid flow, we develop a multidomain electro-osmotic model of optic-nerve microcirculation that couples hydrostatic and osmotic fluid transport with electro-diffusive solute movement across axons, glia, the extracellular space, and arterial/venous/capillary perivascular spaces. Cerebrospinal fluid enters the optic nerve via the arterial parivascular space, passes both the glial and ECS before exiting through the venous parivascular space. Exchanges across astrocytic endfeet are essential and they occur in two distinct and coupled paths: through AQP4 on glial membranes and gaps between glial endfeet, thus establishing a mechanistic substrate for two modes of glymphatic transport, at rest and during stimulus-evoked perturbations. Parameter sweeps show that lowering AQP4-mediated fluid permeability or PVS permeability elevates pressure, suppresses radial exchange and slows clearance, effects most pronounced for solutes reliant on PVS V export. The model reproduces baseline and stimulus-evoked flow and demonstrates that PVS-mediated export is the primary clearance route for both small and moderate solutes. Small molecules clear faster because rapid ECS diffusion broadens their distribution and enhances ECS PVS exchange, whereas moderate species have low ECS diffusivity, depend on transendfoot transfer, and clear more slowly via PVS V convection. Our framework can also be used to explain the sleep-wake effect mechanistically: enlarging ECS volume or permeability increases transinterface flux and accelerates waste removal.