Cell Volume in Brain Pathologies: Anions-Controlled Neural and Glial Swelling in Spreading Depolarization and Increased Neuronal Susceptibility to Ischemic Injury due to Large Extracellular Space

Abstract

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little about the dynamics of cell and tissue swelling, and the differential changes in the volumes of neurons and glia during pathological states such as spreading depolarizations (SD) and epileptic seizures. By combining the Hodgkin-Huxley type spiking dynamics, dynamic ion concentrations, and simultaneous neuronal and astroglial volume changes into a comprehensive model, we elucidate why glial cells swell more than neurons in SD and the special case of ischemia-induced anoxic depolarization (AD). We explore the relative contributions of the two cell types to tissue swelling and our results demonstrate that anion channels, particularly Cl-, are intrinsically connected to cell swelling. Blocking these currents prevents changes in cell volume. Our model is simple, physiologically realistic, and derived from the first physical principles of electroneutrality, osmosis and conservation of particles. We provide new insights into numerous studies related to neuronal and glial volume changes in SD that otherwise seem contradictory. The theory is broadly applicable to swelling in other cell types and conditions.In a complimentary research we found that the brain region-specific extracellular volume fraction has a strong effect on the recoverability of neurons from AD. Glial-vascular K+ clearance and Na+ /K+ -exchange pumps are key to the cell's recovery, and the large extracellular space in the upper brain regions leads to impaired Na+/K+-exchange pumps so that they function at reduced capacity. Hence they are unable to bring the cell out of AD after oxygen and glucose is restored, leading to permanent cell damage.