Myelin Governs Hippocampal Network Function through the Extracellular Space it Occupies, Not Only the Axons it Insulates

Myelin, the multilamellar sheath wrapping neuronal axons, enables saltatory conduction. Beyond electrical insulation, myelin occupies volume, and therefore shapes the extracellular space (ECS) through which interstitial fluid flows and neurotransmitter diffuses. How these two roles interact is unknown. We built a multi-scale model of hippocampal CA1 coupling lattice Boltzmann simulations of ECS flow to detailed networks of reconstructed neurons and glia. Demyelination enlarged the ECS volume fraction from 28 to 43 per cent up to 43 to 70 per cent across layers, lowered tortuosity from about 1.7 to 1.4, raised effective diffusivity from 0.35 to 0.50 of free solution and shortened solute breakthrough times by roughly a third, while raising flow speed yet lowering viscous dissipation. Because transmitter concentration scales inversely with that volume, synaptic driving force fell: postsynaptic potential amplitude declined with wrap count and transmission failed entirely below four of sixteen wraps. In 200-cell networks, demyelination halved firing (pyramidal 7.9 to 4.4 Hz), rendered discharge burst-dominated, reduced band power by up to 8.7-fold and displaced the population state, which a classifier separated at 100 per cent accuracy, whereas an inflammatory glial census left every functional measure unchanged. Driving myelin continuously from intact to 12.5 per cent and back recovered the same threshold near four wraps, and firing rate and spectral power returned fully to baseline. Myelin thus governs circuit function through the space it vacates as well as the axons it insulates, with opposite consequences for clearance and for signalling, a dissociation that may matter in demyelinating disease.