Abstract
Many pathological conditions, such as seizures, stroke, and spreading depression, are associated with substantial changes in ion concentrations in the extracellular space (ECS) of the brain. An understanding of the mechanisms that govern ECS concentration dynamics may be a prerequisite for understanding such pathologies. To estimate the transport of ions due to electrodiffusive effects, one must keep track of both the ion concentrations and the electric potential simultaneously in the relevant regions of the brain. Although this is currently unfeasible experimentally, it is in principle achievable with computational models based on biophysical principles and constraints. Previous computational models of extracellular ion-concentration dynamics have required extensive computing power, and therefore have been limited to either phenomena on very small spatiotemporal scales (micrometers and milliseconds), or simplified and idealized 1-dimensional (1-D) transport processes on a larger scale. Here, we present the 3-D Kirchhoff-Nernst-Planck (KNP) framework, tailored to explore electrodiffusive effects on large spatiotemporal scales. By assuming electroneutrality, the KNP-framework circumvents charge-relaxation processes on the spatiotemporal scales of nanometers and nanoseconds, and makes it feasible to run simulations on the spatiotemporal scales of millimeters and seconds on a standard desktop computer. In the present work, we use the 3-D KNP framework to simulate the dynamics of ion concentrations and the electrical potential surrounding a morphologically detailed pyramidal cell. In addition to elucidating the single neuron contribution to electrodiffusive effects in the ECS, the simulation demonstrates the efficiency of the 3-D KNP framework. We envision that future applications of the framework to more complex and biologically realistic systems will be useful in exploring pathological conditions associated with large concentration variations in the ECS.
Highlights
The brain mainly consists of a dense packing of neurons and neuroglia, submerged in the cerebrospinal fluid which fills the extracellular space (ECS)
In order to investigate the role of ion-concentration dynamics in the pathological conditions, one must measure the spatial distribution of all ion concentrations over time
VCschemes neglect the effects from diffusive currents on the ECS potentials [4, 22, 23], and in previous computational studies we have found the low-frequency components of the ECS potential to be dominated by diffusion effects [4, 24]
Summary
The brain mainly consists of a dense packing of neurons and neuroglia, submerged in the cerebrospinal fluid which fills the extracellular space (ECS). Neurons generate their electrical signals by exchanging ions with the ECS through ion-selective channels in their plasma membranes. During normal signaling, this does not lead to significant changes in local ion concentrations, as neuronal and glial transport mechanisms work towards maintaining ion concentrations close to baseline levels. A better understanding of the electrodiffusive interplay between ECS ion dynamics and ECS potentials may be a prerequisite for understanding the mechanisms behind many pathological conditions linked to substantial concentration shifts in the ECS, such as epilepsy and spreading depression [3, 5,6,7]
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