An electrodiffusive neuron-extracellular-glia model with somatodendritic interactions

Computational modeling in neuroscience has largely focused on simulating the electrical activity of neurons, while ignoring other components of brain tissue, such as glial cells and the extracellular space. As such, most existing models can not be used to address pathological conditions, such as spreading depression, which involves dramatic changes in ion concentrations, large extracellular potential gradients, and glial buffering processes. We here present the electrodiffusive neuron-extracellular-glia (edNEG) model, which we believe is the first model to combine multicompartmental neuron modeling with an electrodiffusive framework for intra- and extracellular ion concentration dynamics in a local piece of neuro-glial brain tissue. The edNEG model (i) keeps track of all intraneuronal, intraglial, and extracellular ion concentrations and electrical potentials, (ii) accounts for neuronal somatic action potentials, and dendritic calcium spikes, (iii) contains a neuronal and glial homeostatic machinery that gives physiologically realistic ion concentration dynamics, (iv) accounts for electrodiffusive transmembrane, intracellular, and extracellular ionic movements, and (v) accounts for glial and neuronal swelling caused by osmotic transmembrane pressure gradients. We demonstrate that the edNEG model performs realistically as a local and closed system, i.e., that it maintains a steady state for moderate neural activity, but experiences concentration-dependent effects, such as altered firing patterns and homeostatic breakdown, when the activity level becomes too intense. Furthermore, we study the role of glia in making the neuron more tolerable to hyperactive firing and in limiting neuronal swelling. Finally, we discuss how the edNEG model can be integrated with previous spatial continuum models of spreading depression to account for effects of neuronal morphology, action potential generation, and dendritic Ca2+ spikes which are currently not included in these models. Author summaryNeurons communicate by electrical signals mediated by the movement of ions across the cell membranes. The ionic flow changes the ion concentrations on both sides of the cell membranes, but most modelers of neurons assume ion concentrations to remain constant. Since the neuronal membrane contains structures called ion pumps and cotransporters that work to maintain close-to baseline ion concentrations, and the brain contains a cell type called astrocytes that contribute in keeping an appropriate ionic environment for neurons, the assumption is justifiable in many scenarios. However, for several pathological conditions, such as epilepsy and spreading depression, the ion concentrations may vary dramatically. To study these scenarios, we need models that account for changes in ion concentrations. In this paper, we present what we call the electrodiffusive neuron-extracellular-glia model (edNEG), which keeps track of all ions in a closed system containing a neuron, the extracellular space surrounding it, and an astrocytic "domain". The edNEG model ensures a complete and consistent relationship between ion concentrations and charge conservation. We envision that the model can be used to study a range of pathological conditions such as spreading depression and, hence, be of great value for the field of neuroscience.