A computational study on the role of glutamate and NMDA receptors on cortical spreading depression using a multidomain electrodiffusion model.

Author summary Cortical spreading depression is a wave of neuronal silencing and ion concentration changes that sweeps slowly through the brain. It is the basis of migraine aura, in which a migraine patient sees a defect move through ones visual field 30 minutes to an hour prior to the headache attack. In this paper, we study the mechanisms by which cortical spreading depression travels as a wave through the brain. We construct a detailed mathematical model based on the physics of ion movement as well as what is known about the molecular players of cortical spreading depression. We build a simulation program that successfully solves the resulting set of highly coupled equations. We find that cortical spreading depression can propagate as a wave by distinct but overlapping mechanisms. We also simulate spiral cortical spreading depression waves and study their properties. Cortical spreading depression (SD) is a spreading disruption of ionic homeostasis in the brain during which neurons experience complete and prolonged depolarizations. SD is the basis of migraine aura and is increasingly associated with many other brain pathologies. Here, we study the role of glutamate and NMDA receptor dynamics in the context of an ionic electrodiffusion model. We perform simulations in one (1D) and two (2D) spatial dimension. Our 1D simulations reproduce the "inverted saddle" shape of the extracellular voltage signal for the first time. Our simulations suggest that SD propagation depends on two overlapping mechanisms; one dependent on extracellular glutamate diffusion and NMDA receptors and the other dependent on extracellular potassium diffusion and persistent sodium channel conductance. In 2D simulations, we study the dynamics of spiral waves. We study the properties of the spiral waves in relation to the planar 1D wave, and also compute the energy expenditure associated with the recurrent SD spirals.