An electrodiffusive, ion conserving Pinsky-Rinzel model with homeostatic mechanisms

In most neuronal models, ion concentrations are assumed to be constant, and effects of concentration variations on ionic reversal potentials, or of ionic diffusion on electrical potentials are not accounted for. Here, we present the electrodiffusive Pinsky-Rinzel (edPR) model, which we believe is the first multicompartmental neuron model that accounts for electrodiffusive ion concentration dynamics in a way that ensures a biophysically consistent relationship between ion concentrations, electrical charge, and electrical potentials in both the intra- and extracellular space. The edPR model is an expanded version of the two-compartment Pinsky-Rinzel (PR) model of a hippocampal CA3 neuron. Unlike the PR model, the edPR model includes homeostatic mechanisms and ion-specific leakage currents, and keeps track of all ion concentrations (Na+, K+, Ca2+, and Cl−), electrical potentials, and electrical conductivities in the intra- and extracellular space. The edPR model reproduces the membrane potential dynamics of the PR model for moderate firing activity. For higher activity levels, or when homeostatic mechanisms are impaired, the homeostatic mechanisms fail in maintaining ion concentrations close to baseline, and the edPR model diverges from the PR model as it accounts for effects of concentration changes on neuronal firing. We envision that the edPR model will be useful for the field in three main ways. Firstly, as it relaxes commonly made modeling assumptions, the edPR model can be used to test the validity of these assumptions under various firing conditions, as we show here for a few selected cases. Secondly, the edPR model should supplement the PR model when simulating scenarios where ion concentrations are expected to vary over time. Thirdly, being applicable to conditions with failed homeostasis, the edPR model opens up for simulating a range of pathological conditions, such as spreading depression or epilepsy.Author summary: Neurons generate their electrical signals by letting ions pass through their membranes. Despite this fact, most models of neurons apply the simplifying assumption that ion concentrations remain effectively constant during neural activity. This assumption is often quite good, as neurons contain a set of homeostatic mechanisms that make sure that ion concentrations vary quite little under normal circumstances. However, under some conditions, these mechanisms can fail, and ion concentrations can vary quite dramatically. Standard models are thus not able to simulate such conditions. Here, we present what to our knowledge is the first multicompartmental neuron model that accounts for ion concentration variations in a way that ensures complete and consistent ion concentration and charge conservation. In this work, we use the model to explore under which activity conditions the ion concentration variations become important for predicting the neurodynamics. We expect the model to be of great value for the field of neuroscience, as it can be used to simulate a range of pathological conditions, such as spreading depression or epilepsy, which are associated with large changes in extracellular ion concentrations.