Abstract
Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.
Highlights
Cells swell during a wide variety of pathologies, including trauma, ischemia, hypoxia, seizures, and spreading depression [1,2,3]
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
By combining the dynamic ion concentrations and volume, conservation of charge, and the energy requirements of the cell within a Hodgkin-Huxley type framework, we demonstrate the feasibility of a comprehensive framework encompassing a wide range of neuronal behaviors
Summary
Cells swell during a wide variety of pathologies, including trauma, ischemia, hypoxia, seizures, and spreading depression [1,2,3]. Pathological states involving excessive neuronal depolarization such as epileptic seizure (SZ), spreading depression (SD), and anoxic depolarization (AD) during ischemia are characterized by major rearrangements of various ions across the cell membrane and neuronal microenvironment [1, 10,11,12,13,14,15,16]. In each of these three conditions, collapse of transmembrane ionic gradients requires enhanced oxygen and glucose consumption required by active transport systems to reestablish the gradients [17, 18]. For the purpose of this paper, we define SZ, SD, and AD respectively as the ion concentrations-induced high-frequency bursts not usually seen in the normal condition of the same cell [1, 19], the nearly complete depolarization of the cell’s membrane potential that recovers spontaneously on the scale of seconds [13, 19], and the nearly complete depolarization of the cell’s membrane potential triggered by oxygen (O2) and glucose deprivation (OGD) that may or may not recover depending on the cell type after O2 and glucose is restored [1, 20, 21]
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