RT Journal Article
SR Electronic
T1 Multiscale computer modeling of spreading depolarization in brain slices
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.20.477118
DO 10.1101/2022.01.20.477118
A1 Craig Kelley
A1 Adam JH Newton
A1 Sabina Hrabetova
A1 Robert A. McDougal
A1 William W Lytton
YR 2022
UL http://biorxiv.org/content/early/2022/01/22/2022.01.20.477118.abstract
AB Spreading depolarization (SD) is a slow-moving wave of neuronal depolarization accompanied by a breakdown of ion concentration homeostasis, followed by long periods of neuronal silence (spreading depression), and associated with several neurological conditions. We developed multiscale (ions to tissue slice) computer models of SD in brain slices using the NEURON simulator: 36,000 neurons (2 voltage-gated ion channels; 3 leak channels; 3 ion exchangers/pumps) in the extracellular space (ECS) of a slice (1 mm sides, varying thickness) with ion (K+, Cl−, Na+) and O2 diffusion and equilibration with a surrounding bath. Glia and neurons cleared K+ from the ECS via Na+/K+pumps. SD propagated through the slices at realistic speeds of 2–5 mm/min, which was augmented by 25–30% in models incorporating the effects of hypoxia or of propionate. In both cases, the speedup was mediated principally by ECS shrinkage. Our model allows us to make the following testable predictions: 1. SD can be inhibited by enlarging ECS volume; 2. SD velocity will be greater in areas with greater neuronal density, total neuronal volume, or larger/more dendrites; 3. SD is all-or-none: initiating K+ bolus properties have little impact on SD speed; 4. Slice thickness influences SD due to relative hypoxia in the slice core, exacerbated by SD in a pathological cycle; 5. Higher neuronal spike rates and faster spread will be observed in the core than the periphery of perfused slice during SD.Significance Spreading depolarization (SD) is a slow moving wave of electrical and ionic imbalances in brain tissue and is a hallmark of several neurological disorders. We developed a multiscale computer model of brain slices with realistic neuronal densities, ions, and oxygenation. Our model shows that SD is exacerbated by and causes hypoxia, resulting in strong SD dependence on slice thickness. Our model also predicts that the velocity of SD propagation is not dependent on its initiation, but instead on tissue properties, including the amount of extracellular space and the total area of neuronal membrane, suggesting faster SD following ischemic stroke or traumatic brain injury.Competing Interest StatementThe authors have declared no competing interest.